Prostenoic acids and esters

ABSTRACT

This disclosure describes derivatives, analogs, and congeners of prostanoic acid having a terminal cyclic moiety in the β-chain which possess the pharmacological activities associated with the prostaglandins.

BACKGROUND OF THE INVENTION

Applicants are not aware of any prior art reference which, in their respective judgments as one skilled in the prostaglandin art, would anticipate or render obvious the novel compounds of the instant invention; however, for the purpose of fully developing the background of the invention and establishing the state of the requisite art, the following references are set forth: U.S. Pat. No. 3,884,969; Japanese Pat. No. 3,884,969; German Offen. No. 2,515,770; German Offen. No. 2,510,818; and Netherlands published Patent Application 7,410-185.

BRIEF SUMMARY OF THE INVENTION

This invention relates to novel prostenoic acids and esters of the formula: ##STR1## wherein R₁ is selected from the group consisting of hydroxy, triloweralkylsilyloxy (C₁ to C₄) and straight or branched chain alkoxy (C₁ to C₆); R₅ is selected from the group consisting of hydrogen, triloweralkylsilyloxy (C₁ to C₄), and alkanoyloxy (C₂ to C₅); Y is a trivalent radical selected from the group consisting of ##STR2## wherein R₃ is selected from the group consisting of hydrogen, and alkanoyl (C₂ to C₅); X is a divalent radical selected from the group consisting of ##STR3## wherein R₄ is selected from the group consisting of a branched or straight chain alkyl group (C₁ to C₇), hydrogen, phenoxy and phenoxy substituted with a compound selected from the group consisting of halogen, trifluoromethyl, and loweralkoxy (C₁ to C₄) groups; n is zero or an integer from 1 to 4; m is zero or an integer from 1 to 4 the sum of n and m has the value of 2 to 4; the moiety C₁₃ -C₁₄ is ethylene or trans vinylene; w is 1 or zero; Z is a divalent radical selected from the group consisting of --(CH₂)_(p) --, ##STR4## --(CH₂)_(t) --O--CH₂ -- and --(CH₂)_(t) -- --S--CH₂ -- wherein p is an integer from 5 to 7, q is an integer from 1 to 3, t is an integer from 3 to 5 and R₅ is hydrogen or lower alkyl group (C₁ to C₃).

DETAILED DESCRIPTION OF THE INVENTION

Useful pharmacologically acceptable salts of the above formula wherein R₁ is hydroxy are those with pharmacologically acceptable metal cations, ammonium, amine cations, or quaternary ammonium cations.

Expecially preferred metal cations are those derived from the alkali metals, e.g., lithium, sodium and potassium, and from the alkaline earth metals, e.g., magnesium and calcium, although cationic forms of other metals, e.g., aluminum zinc, and iron, are within the scope of this invention.

Pharmacologically acceptable amine cations are those derived from primary, secondary, or tertiary amines. Examples of suitable amines are methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, α-phenylethylamine, β-phenylethylamine, ethylenediamine, diethylenetriamine, and the aliphatic, cycloaliphatic, and araliphatic amines containing up to an including about 18 carbon atoms, as well as heterocyclic amines, e.g., piperidine, morpholine, pyrrolidine, piperazine, and lower-alkyl derivatives thereof, e.g., 1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethyl piperazine, 2-methylpiperidine, and the like, as well as amines containing water-solubilizing or hydrophilic groups, e.g., mono-, di, and triethanolamine, ethyldiethanolamine, N-butylethanolamine, 2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, tris(hydroxymethyl)aminomethane, N-phenylethanolamine, N-(p-tert-amylphenyl)diethanolamine, galactamine, N-methylglucamine, N-methylglucosamine, ephedrine, phenylephrine, epinephrine, procaine, and the like.

Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium, and the like.

The compounds of this invention are administered in various ways for various purposes, e.g., intravenously, intramuscularly, subcutaneously, orally, intravaginally, rectally, bucally, sublingually, topically and in the form of sterile implants for prolonged action.

For intravenous injection or infusion, sterile aqueous isotonic solutions are preferred. For that purpose, it is preferred because of increased water solubility that R₁ be hydrogen or a pharmacologically acceptable cation. For subcutaneous or intramuscular injection, sterile solutions or suspensions of the acid, salt, or ester formed in aqueous or non-aqueous media are used. Tablets, capsules, and liquid preparations such as syrups, elixirs, and simple solutions, with the usual pharmaceutical carriers are used for oral or sublingual administration. For rectal or vaginal administration, suppositories prepared as known in the art are used. For tissue implants, a sterile tablet or silicone rubber capsule or other object containing or impregnated with the substance is used. On certain occasions it may be advantageous to administer the compounds of this invention as clathrate compounds with substances such as α-cyclodextrin.

The prostaglandins are a family of closely related compounds which have been obtained from various animal tissues and which stimulate smooth muscle, lower arterial blood pressure, antagonize epinerphrine-induced mobilization of free fatty acids, and have other pharmacological and autopharmacological effects in mammals. See Bergstom, et al., J. Biol. Chem., 238, 3555 (1963) and Horton, Experientia, 21, 113 (1965) and references cited therein. All of the so-called natural prostaglandins are derivatives of prostanoic acid: ##STR5## The hydrogen atoms attached to C-8 and C-12 are in trans-configuration. The natural prostaglandins represent only one of the possible optical isomers. The compounds of this invention include all possible optical isomers.

The compounds of this invention which have the structure as shown in formula (A) wherein R₁, Z, Y, m, n, w and X are as hereinabove defined are said to be in the same configuration as the natural prostaglandins with respect to the configurations at C₈, C₁₁ and C₁₂ and are designated by the prefix nat. The enantiomer, represented by formula (B) is said to be in the mirror image or ent configuration. A hydroxy group at C₁₁ drawn with a dotted line (C₁₁ ---OH) is said to have an α configuration; a solid line (C₁₁ OH) indicates a β configuration. The configuration at Y and X will be expressed in terms of R and S as is understood in the art. For example, the compound represented by formula (C) is named: nat-15S,16S-9α,15-dihydroxy-11-oxo-15,16-trimethylene-13-trans-prostenoic acid; its enantiomer (formula D) is named ent-15R,16R-9α,15-dihydroxy-11-oxo-15,16-trimethylene-13-trans-prostenoic acid. The racemate [1:1 mixture of (C) and (D)] is named nat-15 S,16S-(and ent-15R,16R)9α,15-dihydroxy-11-oxo-15,16-trimethylene-13-trans-prostenoic acid. In a similar manner, the compounds represented by formulae (E) to (J) the configurations shown below. ##STR6##

In each of the above formulae (C to J) the hydroxy group at C₉ is named "-9α-hydroxy".

The novel compounds of this invention can be prepared by the reaction sequences illustrated in Flowsheet A below, wherein n, m, X, w, and Z are as hereinabove defined; R₁ ' is straight or branched-chain alkoxy (C₁ to C₁₂) or triloweralkylsilyloxy (C₁ to C₄); R₂ ' is triloweralkylsilyloxy (C₁ -C₄) or alkanoyloxy (C₂ to C₅); R₁ " and R₂ " are hydroxy. ##STR7##

In accordance with the scheme as outlined hereinabove in Flowsheet A a ketone (I) is reacted with a Grignard reagent (II) such as acetylene magnesium chloride (II, w=0) or propargyl magnesium bromide (II, w=1) to give the acetylenic alcohols (III). In those cases where X is not --CH₂ -- two isomeric acetylenic alcohols are formed. These isomers can be separated by procedures well known to the art including fractional crystallization, fractional distillation and various chromatographic procedures. The individual isomers can then be carried through the remaining reactions outlined in Flowsheet A.

The acetylenic alcohol (III) is converted to its trimethylsilyl ether in the usual manner. The silylated derivative (IV) is then treated with diisoamylborane (prepared in situ in tetrahydrofuran solution at ice bath temperatures from 2-methyl-2-butene, sodium borohydride and boron trifluoride ethereate) and then anhydrous trimethylamine oxide. The resulting solution and an iodine solution in tetrahydrofuran are then added simultaneously to an aqueous solution of sodium hydroxide to give the 1-iodo-3-trimethylsilyloxy-trans-1-alkene (V).

The vinyl iodide (V) is converted to the trans-vinyl lithium derivative (VII) with clean retention of configuration by treatment at about -78° C. in hexane or toluene solution with either one equivalent of n-butyl lithium or two equivalents of t-butyl lithium. It is preferable for this treatment to proceed for about one hour at -78° C., then for about one hour at -40° C. and finally for about one hour at about 0° C. For the subsequent preparation of lithio alanate reagents (VIII) it is preferable to use n-butyl lithium, and for the lithio cuprate reagents (IX) or (X) t-butyl lithium is the agent of choice. The same vinyl lithium derivative (VII) can be prepared from the 1-tri-n-butylstannyl 3-trimethylsilyloxy-trans-1-alkene (VI) by treatment of (VI) with n-butyl lithium in hexane solution at -40° to 0° C. (VI) in turn is readily prepared by the addition of tri-n-butyl tin hydride to the acetylene (IV) in the presence of bisazoisobutyronitrile followed by vacuum distillation at a high enough temperature (about 170° C.) to isomerize any of the cis-vinyl tin compound to the trans-vinyl tin compound.

For the preparation of the alanate reagent (VIII) or the like, a molar equivalent of a tri-lower alkyl (1-5 carbon atoms) aluminum (e.g., trimethyl aluminum), dissolved in a solvent such as hexane, is added to the vinyl lithium derivative (VII) at about 0° C. After about 15-45 minutes at this temperature the requisite blocked cyclopentenone (XI) is added and the reaction mixture is stirred for about 18 hours at ambient temperatures. The mixture is quenched with aqueous hydrochloric acid in the cold and the product is obtained by extraction. In the 11-deoxy series the blocking trialkylsilyl group is removed on treatment with acetic acid:tetrahydrofuran:water (4:2:1) at room temperatures for about twenty minutes. The ester group can then be saponified in the usual manner. In the 11-oxy series, the silyl groups are removed by treatment with acetic acid:water:tetrahydrofuran (20:10:3) at about 40° C. for about 4 hours. Alkyl esters of the 11-oxy series are not disturbed by this treatment and cannot be saponified by chemical means in view of the instability of the 11-hydroxy-9-ketone to base treatment. However, the ester can be cleaved by treatment with Baker's Yeast, a procedure well-known in the art.

For the preparation of the asymmetrical lithio cuprate (IX) or the like, a solution of one molar equivalent of copper (I)-1-alkyne, preferably copper (I)-1-pentyne, in anhydrous hexamethylphosphorous triamide, preferably three to five molar equivalents, and anhydrous ether is added to one molar equivalent of the aforementioned vinyl lithium (VII) solution cooled to about -78° C. The solution is then stirred for about one hour at -78° C. A cuprate reagent containing a p-thiophenoxide ligand ##STR8## can also be used; it is prepared by first forming lithium thiophenoxide by adding an equivalent of n-butyl lithium in hexane to an etheral solution of thiophenol. To this is then added a solution of one equivalent of tri-n-butyl phosphine copper iodide complex in ether. The resulting solution of phenylthio copper is added at -78° C. under inert gas to the solution of the vinyl lithium compound (VII). The mixture is then maintained at -78° C. for one hour. To either of these cuprate solutions at -78° C. a molar equivalent of the requisite cyclopentenone (XI) is added. After several hours at -20° C. the reaction mixture is quenched with aqueous ammonium chloride solution and the blocked product (XII) is isolated in the usual manner. The deblocking of this product is then carried out in the manner as described hereinabove.

The products are finally purified by chromatographic procedures in the usual manner.

In those cases where X is not CH₂ and m≠n-1, two isomers are formed which differ in the configuration at C₁₅ (w=0) or C₁₆ (w=1); both isomers are racemates and they can be separated from each other by chromatographic procedures well known to the art.

For the preparation of the symmetrical lithio cuprate (X) one molar equivalent of copper (I) iodide tributyl-phosphine complex, dissolved in anhydrous ether, is added at about -78° C. to two molar equivalents of the aforementioned vinyl lithium (VII) solution in hexanes, cooled to -78° C. After about one hour at this temperature, the lithio cuprate (X) is treated with the requisite cyclopentenone (XI) as described hereinabove for the conjugate addition with the 1-alkynyl lithio cuprate (IX).

In order to ensure a trans-relationship in (XII), (XIV) or (XIII), these products can be submitted to conditions known in the literature to equilibrate cis 8-iso-PGE₁ to a mixture containing about 90% of the trans-product [see E. G. Daniels, et al., J. A. C. S., 90, 5894 (1968)]. These conditions involve treatment with potassium acetate in aqueous methanol for about 96 hours at room temperature. The cis and trans products are separable by chromatographic procedures.

Most of the cyclopentenones required for the purposes of this invention have been described in the literature or can be prepared by procedures quite analogous to those already described. Appropriate references are provided in the examples which follow. The synthesis of certain non-reference requisite cyclopentenones is also described therein.

The 9-keto derivatives (XIV) or (XIII) of this invention can be converted to the corresponding 9-hydroxy derivatives. If this conversion is effected with sodium borohydride, the product is a mixture of 9α- and 9β-hydroxy derivatives (prostaglandins of the Fα and Fβ series, respectively): (XIX) and (XX), respectively, from (XIV) and (XXI) and (XXII), respectively, from (XIII). The 9α and 9β derivatives are separable from each other by chromatographic procedures well-known in the art.

When the reduction is carried out with lithium perhydro-9b-boraphenalyl hydride [H. C. Brown and W. C. Dickason, J. A. C. S., 92, 709 (1970)] or with lithium tri(sec-butyl)borohydride [H. C. Brown and S. Krishnamurthy ibid., 94, 7159 (1972)], the product is at least predominantly the 9-hydroxy derivative (XIX) or (XXI), wherein the 9-hydroxy group is cis to the side-chain attached to C₈ and to the 11-oxy function, if present. In accordance with accepted convention, an α-substituent at the 8-, 9-, 11- or 12-positions is behind the plane of the paper whereas a β-substituent at these positions is in front of the plane of the paper. This is usually represented by a bond for an α-substituent, a bond for a β-substituent, and a bond where both possibilities are indicated.

The 13-dihydro derivatives (C₁₃ -C₁₄ is ethylene) of this invention can be prepared by reduction of the Δ¹³ function in the corresponding 13-prostenoic acids or esters. This reduction can be accomplished by catalytic reduction, preferably at low pressure with a noble metal catalyst in an inert solvent at ambient temperatures.

The 11-oxo-9α hydroxy derivatives (XXIII) and (XXIV) (prostaglandins of the D series) can readily be prepared by oxidation of the respective 9α-hydroxy derivatives (XXI) and (XIX) with Jones reagent at -35° C. in acetone. This oxidation procedure is selective and gives (XXIII) or (XXIV) contaminated with only small amounts of the 9-oxo derivatives (XIII) or (XIV) respectively from which they can be separated by chromatography.

The prostanoic and prostenoic carboxylic acids of this invention are convertible to the corresponding alkyl esters by treatment with the appropriate diazoalkane in the usual manner. The preparation of diazoalkanes by various procedures are well-described in the art, see for example C. D. Gutsche, Organic Reactions, VIII, 389 (1954). Certain of the esters of this invention can also be obtained directly by use of the appropriate cyclopentenone ester (see XI). The various esters can also be prepared by any of several procedures well-known in the art via an acid chloride (prior blocking of free alcohol groups with appropriate blocking groups such as trialkylsilyl, tetrahydropyranyl and the like) or mixed anhydrides and treatment of these intermediates with the appropriate alcohol. Mixed anhydrides can be obtained by treatment of the prostaglandin acid in a solvent such as dioxane at a temperature in the range of 0° C. to 15° C. with a molar equivalent of a tri-alkylamine, preferably triethylamine, tributylamine and the like, and then a molar equivalent of isobutyl chlorocarbonate or the like. The resulting mixed anhydride is then treated with the appropriate alcohol to give the derivatized product. [For a pertinent literature analogy see Prostaglandins, 4, 738 (1973).]

An alternative procedure involves treatment of the prostaglandin acid with a molar equivalent of the trialkyl amine in an excess of the appropriate alcohol in an anhydrous solvent such as methylene chloride, a molar equivalent of p-toluenesulfonyl chloride is then added (if necessary, a second molar equivalent can be added) and after stirring at ambient temperatures for about 15 minutes to one hour the product is worked-up in the usual manner. (For a pertinent literature analogy see U.S. Pat. No. 3,821,279, June 28, 1974). A third procedure involves use of dicyclohexylcarbodiimide in the usual manner; for a pertinent literature analogy see German Offen. No. 2,365,205 (July 11, 1974); Chem. Abst., 81, 120098 g. (1974).

The esterified alcohol derivatives C₉ --OR₃, R₃ is alkanoyl) are also prepared in the usual manner by procedures well-known in the art form the appropriate alkanoic acid anhydride or acid chloride.

Certain of the ketones (I) of this invention are prepared as indicated in Flowsheet B below:

FLOWSHEET B ##STR9## wherein n and m are as hereinabove defined and the moiety ##STR10## represents a phenoxy group which is optionally substituted with one or more halogen, trifluoromethyl, and lower alkyloxy (C₁ to C₄) groups.

As indicated in Flowsheet B the reaction of an epoxide (XXV) with a substituted or unsubstituted phenol (XXVI) in the presence of a catalytic amount of aqueous sodium hydroxide and a phase transfer catalyst such as methyl tricapryly ammonium chloride and the like at 70°-80° C. gives the phenoxy substituted alcohol (XXVII) which in turn is oxidized with an oxidizing reagent such as pyridinium chlorochromate in methylene chloride to give the phenoxy substituted ketone (XXVIII).

The other ketones (I) used in this invention are known in the literature or can be made by procedures well known to the art [G. Lardelli, U. Lamberti, W. T. Walles and A. P. de Jonge, Rec. Trav. Chem. Pays-Bas, 86 481 (1967); Ng. Ph. Buu-Hoi, T. B. Loc and Ng. Dat Xuong., Bull. Soc. Chem. France, 174 (1958); and G. H. Posner, Organic Reactions, 19, 1 (1972)].

Also embraced within the scope of this invention are the various intermediates, the use of which is described herein. These are represented by the following generic formulae (K) and (L). ##STR11## Wherein w, n, m and x are as hereinabove defined; R₆ is lower alkyl (C₁ to C₆); Q is iodine, triloweralkyl (C₁ -C₆) tin, lithium, ##STR12## R₇ is lower alkyl (C₁ -C₇).

When the compounds of this invention are prepared from racemic starting compounds two racemates are obtained. In appropriate instances these racemates can be separated from each other by careful application of the usual chromatographic procedures. In the more difficult instances it may be necessary to apply high pressure liquid chromatography including recycling techniques. [See G. Fallick, American Laboratory, 19-27 (August, 1973) as well as references cited therein. Additional information concerning high speed liquid chromatography and the instruments necessary for its application is available from Waters Associate, Inc., Maple St., Milford, Mass.]

It is also possible to prepare the individual enantiomers in the 11-oxy series via the conjugate addition procedure discussed above by starting with a resolved 4-oxycyclopentenone [see (XI), R₂ ' is tri-loweralkylsilyloxy]. The resulting products (XIV) and (XIII) after deblocking as described hereinabove are obtained in their optically active forms.

The 4-hydroxycyclopentenone racemates may be resolved into their component enantiomers (XXXI) and (XXXII) by derivatizing the ketone function with a reagent having an optically active center. The resulting diastereomeric mixture can then be separated by fractional crystallization, or by chromatography, or by high speed liquid chromatography involving, if necessary, recycling techniques. Among the useful optically active ketone derivatizing reagents are 1-α-aminoxy- -methylpentanoic acid hydrochloride [to give (XXXIII)], (R)-2-aminoxy-3,3-dimethylbutyric acid hydrochloride, and 4-α-methylbenzyl semicarbazide. After separation of the diastereomeric derivatives, reconstitution of the keto function provides the individual 4-hydroxycyclopentenone enantiomers (XXXI) and (XXXII). A useful procedure for the resolution of a 4-hydroxycyclopentenone racemate via an oxime such as (XXXIII) is described in the art [R. Pappo, P. Collins and C. Jung, Tetrahedron Letters, 943 (1973)]. ##STR13##

An alternative procedure for the preparation of the 4(R)-hydroxycyclopentenone enantiomers such as (XXXI) involves as a key step the selective microbiological or chemical reduction of trione (XXXIV) to the 4(R)-hydroxycyclopentanedione (XXXV). A wide variety of microorganisms are capable of accomplishing this asymmetric reduction, one of the most useful being Dipodascus unincleatus. This step also can be achieved chemically by catalytic hydrogenation in the usual manner (for example, under about one atmosphere of hydrogen in methanol) using a soluble rhodium catalyst with chiral phosphine ligands, such as (1,5-cyclooctadiene)-bis-(o-anisylcyclohexylmethylphosphine)rhodium (I) tetrafluoroborate in the presence of one equivalent of organic base, such as triethylamine.

Conversion of hydroxycyclopentanedione (XXXV) to an enol ether or enol ester, (XXXVI, E=alkyl, preferably iso-propyl; aroyl such as benzoyl; or arylsulfonyl such as 2-mesitylenesulfonyl), is accomplished by treatment, for example, with isopropyl iodide and a base such as potassium carbonate in refluxing acetone for from 15 to 20 hours, or with a base such as triethylamine and 0.95 equivalents of benzoyl chloride or a slight excess of 2-mesitylenesulfonyl chloride, in a non-prototropic solvent at a temperature of about -10° to -15° C. Reduction of (XXXVI) with excess sodium bis(2-methoxyethoxy)aluminum hydride in a solvent such as tetrahydrofuran or toluene at low temperatures, such as -60° to -78° C., followed by mild acid hydrolysis (representative conditions: aqueous dilute hydrochloric acid, pH 2.5; or oxalic acid, sodium oxalate in chloroform) at ambient temperatures from 1 to 3 hours provides the 4(R)-hydroxycyclopentenone ester (XXXVII). The ester (XXXVII), after blocking the hydroxy function as described hereinabove, can be subjected to conjugate addition reactions also as described hereinabove. The conjugate addition product, after deblocking the 11- and 15-hydroxy groups, will then be a methyl ester which can be hydrolyzed to the corresponding carboxylic acid by enzymatic or microbiological procedures, for example with baker's yeast or by exposure to Rhizopus oryzae.

For a description of these procedures in the art see: C. J. Sih, et al, J. A. C. S., 95, 1676 (1973); J. B. Heather, et al., Tetrahedron Letters, 2213 (1973); R. Pappo and P. W. Collins, Tetrahedron Letters, 2627 (1972); and R. Pappo, P. Collins, and C. Jung, Ann. N. Y. Acad. Sci., 180, 64 (1971). For a description of the baker's yeast procedure see C. J. Sih, et al., J. A. C. S., 94, 3643 (1972). ##STR14##

Procedures for the preparation of the requisite cyclopentanetriones (XXXIV) are well-established in the art and generally involve the treatment of an -1 oxo long chain ester (XXXVIII) with methyl or ethyl oxalate and a base such as sodium methoxide in methanol, followed by treatment with dilute hydrochloric acid in aqueous methanol to effect the dealkoxalylation of the intermediate (XXXIX). See J. Kutsube and M. Matsui, Agr. Biol. Chem., 33 1078 (1969); P. Collins, C. J. Jung and R. Pappo, Israel Journal of Chemistry, 6, 839 (1968); R. Pappo, P. Collins and C. Jung, Ann. N.Y. Acad. Sci., 180, 64 (1971); C. J. Sih, et al., J. A. C. S., 95, 1676 (1973) (see reference 7); and J. B. Heather, et al., Tetrahedron Letters, 2313 (1973) for pertinent background literature. ##STR15##

The intermediate keto esters (XXXVIII) may be prepared by a variety of methods known to the art. One useful procedure is outlined below and involves alkylation of ethyl acetoacetate sodium salt (XL) in the usual manner with the appropriate side-chain precursor (XLI, X=Cl, Br, I, preferably Br or I) followed by decarbethoxylation and reesterification, all in the usual manner. ##STR16##

The side-chain precursors (XLI) are commercially available where Z is --(CH₂)_(p) --, and can be prepared as described in Belgian Pat. No. 786,215 (granted and opened to inspection Jan. 15, 1973).

Those precursors wherein Z is --(CH₂)_(t) --O--CH₂ -- can be prepared by the transformation shown directly below starting with the mono-tetrahydropyranyl derivative (XLIV). Thus, (XLIV) is converted to the lithium alcoholate by treatment with butyl lithium, the alcoholate is then O-alkylated with ethyl bromoacetate to provide (XLV), which on de-O-tetrahydropyranylation, mesylation and reaction with lithium bromide gives the required (XLVI). (These and all the above-described transformations can be effected in the usual manner, well-established in the art; pertinent examples for most of the reactions can be found in the above-cited Belgian Pat. No. 786,215.) ##STR17##

It is also possible to resolve the 4-hydroxycyclopentenone racemate (XLIX) by microbiological means. Thus, treatment of the 4-O-alkanoyl or aroyl derivatives (L, R₁₈ =aryl or alkyl) of racemate (XLIX) (preferably the 4-O-acetyl and 4-O-propionyl derivatives) with an appropriate microorganism, preferably a Saccharomyces species e.g., 1375-143, affords preferential de-O-acylation of the 4(R)-enantiomer to give (LI), which is then separated from the unreacted 4(S)-O-acyl enantiomer (LII) by chromatographic procedures. After separation, mild hydrolysis of the 4(S) derivative (LII) provides the 4(S)-hydroxycyclopentenone (LIII). [See N. J. Marsheck and M. Miyano, Biochima et Biophysica Acta, 316, 363 (1973) for related examples.] ##STR18##

It is also possible to prepare the individual 4-hydroxycyclopentenones (LI) and (LIII) directly by selective microbial hydroxylations of the corresponding 4-unsubstituted cyclopentenone (LIV). For example, with Aspergillus niger ATCC 9142; a selective 4(R)-hydroxylation of [LIV, Z=(CH₂)₆ ] has been reported; see S. Kurozumi, T. Tora and S. Ishimoto, Tetrahedron Letters, 4959 (1973). Other microorganisms can also accomplish this hydroxylation. ##STR19##

An alternative resolution procedure involves derivatization of the alcohol function of the racemic hydroxycyclopentenone to give ester-acid derivatives such as (LV) wherein R₁ " is hydrogen or an alkoxy group, n' is zero or two and Z is as hereinabove defined. ##STR20## Such derivatives may be obtained from the corresponding free hydroxycyclopentenone by treatment in the usual manner with oxalyl chloride, succinyl chloride, succinic anhydride and the like. Treatment of the resulting acid or diacid (R₁ "=hydrogen) with optically active amines e.g., l-(-)-α-methylbenzylamine, d-(+)-α-methylbenzylamine, brucine, dehydroabietylamine, strychnine, quinine, cinchonine, quinidine ephedrine, (+)-α-amino-1-butanol and the like, and fractional recrystallization of the resulting diastereomeric mixtures followed by cleavage of the 4-oxy ester function in each of the individually isolated diastereomers provides the individual 4(R)- and 4(S)-hydroxycyclopentenone enantiomers (LVI) and (LVII) or their respective esters. Cleavage of the oxalate acid ester (LV, n=0) can be accomplished by treatment with lead tetraacetate in pyridine solution. For an example of a similar use of oxalate acid-esters see J. G. Molotkovsky and L. D. Bergelson, Tetrahedron Letters, 4791 (No. 50, 1971); For an example of the use of a succinate acid-ester see B. Goffinet, Ger. Offen. No. 2,263,880; Chem. Abstracts, 79, 7815_(z) (1973).

Resolution of a 9-hydroxy racemate (the component enantiomers are illustrated by LVIII and LIX below) may be accomplished by conversion of the racemate, wherein C₁₁ and C₁₅ or C₁₆ hydroxy functions have been preferentially blocked by trialkylsilyl groups, (for example, by first derivatizing the two hydroxy functions in the corresponding 9-oxo derivative and then reducing the 9-carbonyl as described hereinabove), to the corresponding phthalate half acid-ester, deblocking the C₁₁ and C₁₅ hydroxy functions and conversion of the di-acid (e.g., LX) to a mixture of diastereomeric bis salts (e.g., LXI) with an optically active amine (e.g., 1-(-)-α-methylbenzylamine, D-(+)-α-methylbenzylamine, brucine, dehydroabietylamine, strychnine, quinine, cinchonine, cinchonidine, quinidine, ephedrine, deoxyephedrine, amphetamine, (+)-2-amino-1-butanol, (-)-2-amino-1-butanol and the like). The resulting diastereomers are then separated by fractional crystallization and the individual components are then converted by acidification and saponification to the individual optically active parent 9α-hydroxy enantiomers (LVIII) and (LIX), oxidation of which, after preferential blocking of the C₁₁ and C₁₅ hydroxy functions with tetrahydropyranyl or trialkylsilyl groups, provides, after deblocking, the corresponding individual 9-oxo enantiomers (LXII) and (LXIII). If necessary, the 11- and 15-hydroxy groups can be converted to tetrahydropyranyloxy groups prior to saponification of the phthalate ester. (For an appropriate literature procedure see E. W. Yankee, C. H. Lin and J. Fried, Journ. Chem. Soc., 1972, 1120). ##STR21##

Another procedure involves conversion of the 9α-hydroxy racemate (as the prostenoic acid ester and with the C₁₁ and C₁₅ or C₁₆ alcohol functions preferentially blocked as trialkylsilyl ethers) to the disastereomeric carbamates with an optically active isocyanate, e.g., (+)-1-phenylethylisocyanate or (-)-1-phenylethylisocyanate, followed by deblocking. Separation of the resulting diastereomers, for example (LXIV) and (LXV), can be accomplished by fractional crystallization or by the usual chromatographic procedures, or if necessary by high speed liquid chromatography involving, if necessary, recycling techniques. Base-treatment of the individual diastereomeric carbamates affords the individual diastereomeric alcohols, for example (LVIII) and (LXVI). There in turn can be oxidized to the corresponding 11-oxo compounds claimed in this invention (LVII b) and (LXVI b). ##STR22##

It is also possible to effect resolution of the 9α-hydroxy racemate, preferably as the prostenoate ester, by esterification of the 9α-hydroxy function (prior preferential blocking as discussed hereinabove of C₁₁ and C₁₅ or C₁₆ -hydroxy functions as tetrahydropyranyl or trialkylsilyl ethers) with an optically active acid, via its acid chloride followed by deblocking the C₁₁ and C₁₅ or C₁₆ alcohol groups. Suitable optically active acids include ω-comphoric acid, menthoxyacetic acid, 3α-acetoxy-Δ⁵ -etianic acid, (-)-α-methoxy-α-trifluoromethylphenylacetic acid and (+)-α-methoxy-α-trifluoromethylphenylacetic acid, and the like. The resulting diastereomeric esters, for example, (LXVII) and (LXVIII), are then separated by fractional crystallization or by chromatographic techniques including, if necessary, the use of high speed liquid chromatography. Saponification of the individual diastereomers then provides the individual 9α-hydroxyprostenoic acid enantiomers (LVIII) and (LXVI). ##STR23##

Although the above-described procedures are illustrated with examples having the 11α-hydroxy group, they apply as well to the members of the 11-deoxy series.

Other useful ketone derivatizing agents are optically active 1,2-glycols, e.g., D(-)-2,3-butanediol, or 1,2-dithiols, e.g., L(+)-2,3-butanedithiol. These are used to convert the 9-oxo racemate to 9,9-alkylenedioxa or 9,9-alkylenedithia diastereomers. Separation of diastereomers by chromatographic procedures, followed by regeneration of the individual 9-oxo enantiomer by ketal cleavage can be accomplished by procedures well-known in the art. Both ketalization and deketalization would have to be accomplished by procedures which would not disrupt the 11-oxo-9-keto system.

The preparation of the requisite cyclopentenones which contain a sulfur atom in the α-chain is described in Flowsheet C. In accordance with Flowsheet C wherein t is hereinabove described, treatment of 2-furyllithium (LXXIII) with a ω-chloroaldehyde (LXXIV) provides the chloroalcohol (LXXV). Treatment of the chloroalcohol (LXXV) with ethylmercaptoacetate furnishes the hydroxy ester (LXXVI) which upon hydrolysis with sodium formate/formic acid provides the 3hydroxy-cyclopentenone (LXXVII). Treatment of the cyclopentenone (LXXVII) with sulfuric acid provides the required 4-hydroxy-cyclopentenone (LXXVIII) which after treatment with chlorotrimethylsilane and hexamethyl disilazene in pyridine provides the bissilylated cyclopentenone (LXXIX).

The 3-hydroxy-cyclopentenones of the type (LXXVII), the 4-hydroxy-cyclopentenones of the type (LXXVIII), and the bissilylated or bistetrahydropyrayl protected or other suitably protected 4-hydroxy-cyclopentenone of the type (LXXIX) are novel and useful compounds which are also embraced by this invention, as are the novel intermediates required for their preparation. ##STR24##

The ring system of certain of the novel compounds of this invention allow them to be characterized as follows: ##STR25##

The novel compounds of this invention possess the pharmacological activity described below as associated with the appropriate above-described prostaglandin type.

The known PGD compounds are all potent in causing multiple biological responses even at low doses. Moreover, for many applications, these known prostaglandins have an inconveniently short duration of biological activity. In striking contrast, the novel prostaglandin anologs of this invention are substantially more specific with regard to potency in causing prostaglandin-like biological responses, and/or having a substantially, longer duration of biolical activity. Therefore, each of these novel prostaglandin analogs is surprisingly and unexpectedly more useful than one of the corresponding above-mentioned known prostaglandins for at least one of the pharmacological purposes indicated below for the latter, either because it has a different and narrower spectrum of biological activity then the known prostaglandins, and therefore is more specific in its activity and causes smaller and fewer undesired side effects than the known prostaglandins, or because of its prolonged activity, fewer and smaller doses of the novel prostaglandin analog can frequently be used to attain the desired result.

Another advantage of the novel compounds of this invention, compared with the known prostaglandins, is that these novel compounds are administered effectively, orally, sublingually, intravaginally, bucally, or rectally, in addition to the usual intravenous, intramuscular, or subcutaneous injection or infusion methods indicated above for the uses of the known prostaglandins. These qualities are advantageous because they facilitate maintaining uniform levels of these compounds in the body with fewer, shorter, or smaller doses, and make possible self-administration by the patient.

The PGD compounds, and their esters and pharmacologically acceptable salts, are extremely potent in causing various biological responses. For that reason, these compounds are useful for pharmacological purposes. See, for example, Bergstrom, et al., Pharmacol. Rev., 20, 1 (1968), and references cited therein. The PGD compounds show a useful decrease of blood platelet adhesiveness as shown by platelet-to-glass adhesiveness, and inhibition of blood platelet aggregation and thrombus formation induced by various physical stimuli, e.g., arterial injury, and various biochemical stimuli, e.g., ADP, ATP, serotonin, thrombin, and collagen.

Because of these biological responses, these known prostaglandins are useful to study, prevent, control, or alleviate a wide variety of disease and undesirable physiological conditions in birds and mammals, including humans, useful domestic animals, pets, and zoological specimens, and in laboratory animals, for example, mice, rats, rabbits and monkeys.

The PGD compounds are useful whenever it is desired to inhibit platelet aggregation, to reduce the adhesive character of platelets, and to remove or prevent the formation of thrombi in mammals, including man, rabbits, and rats. For example, these compounds are useful in treatment and prevention of myocardial infarcts, to treat and prevent post-operative thrombosis. For these purposes, these compounds are administered systemically, e.g., intravenously, subcutaneously, intramuscularly, and in the form of sterile implants for prolonged action. For rapid response, especially in emergency situations, the intravenous route of administration is preferred Doses in the range of about 0.005 to about 20 mg/kg of body weight per day are used, the extract dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.

The PGD compounds are useful as hypotensive agents to reduce blood pressure in mammals including man. For this purpose, the compounds are administered by intravenous infusion at the rate about 0.01 to about 50 μg per kg of body weight per minute, or in a single or multiple doses of about 25 to 2500 μg per kg of body weight total per day.

The PGD compounds are useful for controlling the reproductive cycle in ovulating female mammals, including humans and other animals. for that purpose, PGD₂, for example, is administered systematically at a dose level in the range of 0.01 mg to about 100 mg per kg of body weight, advantageously during a span of time starting approximately at the time of ovulation and ending approximately at the time of menses or just prior to menses. Additionally, expulsion of an embryo or fetus is accomplished by similar administration of the compound during the first third or the second third of the normal mammalian gestation period. Accordingly they are useful as abortifacients. They are also useful for induction of menses during approximately the first two weeks of a missed menstrual period and accordingly are useful as contraceptive anti-fertility agents.

The novel compounds of this invention induce the biological responses described hereinabove as associated with its particular prostaglandin type. These novel compounds are accordingly useful for the above-described corresponding purposes in the same manner as described above.

These derivatives described hereinabove are also more selective in their biological action and induce a more prolonged effect than the corresponding natural prostaglandins. These preparations are novel, completely unanticipated and provide distinct and important advantages.

In addition, certain of the novel compounds of this invention are useful for the preparation of other novel compounds of this invention.

It is well known that platelet aggregation inhibitors may be useful as anti-thrombotic drugs. Inhibition of platelet aggregation can be conveniently measured in vitro by monitoring changes in optical density and/or light transmission in platelet rich plasma upon addition of suitable aggregating agents such as adenosine diphosphate, epinephrine, thrombin or collagen. Alternatively, platelet aggregation can be measured in vitro using platelet rich plasma obtained at various time intervales from animals given inhibitors by an oral or parenteral route.

The compounds of the present invention exhibit the ability to inhibit platelet aggregation in vitro when tested by the following procedure.

Human protein rich plasma is incubated with modified Tyrode's solution in a proportion of 40-50% human protein rich plasma. The test compounds are added at varying concentrations and after 5 minutes incubation, an aggregating agent such as adenosine diphosphate or collagen is added. The change in optical density (light transmission) is monitored by eye and inhibition is recorded as a (-) or lack of inhibition is recorded as a (+). Test compounds are considered active if they inhibit adenosine diphosphate or collagen induced aggregation at a concentration of 25 mcg/ml or less within 5-10 minutes. The results of this test on representative compounds of this invention appear in Table A.

                                      TABLE A                                      __________________________________________________________________________     Inhibition of Platelet Aggregation-In Vitro                                                         Adenosine Diphosphate                                                                      Collagen                                                           Drug Concentration                                                                         Drug Concentration                                                 ug/ml        ug/ml                                        Compound             250                                                                               25 2.5                                                                               0.25                                                                              250                                                                               25 2.5                                                                               0.25                                 __________________________________________________________________________     nat(and ent)-9α ,15-Dihydroxy-11-oxo-15,16-                              tetramethylene-17,18,19,20-tetranor-13-                                        trans,5-cis-prostadienoic acid                                                                      (-)                                                                               (-)                                                                               (-)                                                                               (+)                                                                               (-)                                                                               (-)                                                                               (-)                                                                               (+)                                  nat(and ent)-9,11,15-trihydroxy-15,16-                                         tetramethylene-17,18,19,20-tetranor-13-                                        trans-5-cis-prostadienoic acid                                                                      (-)                                                                               (+)                                                                               (+)                                                                               (+)                                                                               (-)                                                                               (-)                                                                               (+)                                                                               (+)                                  __________________________________________________________________________      (-) = Inhibition                                                               (+) = No Inhibition                                                      

The novel compounds of the present invention are useful as hypotensive agents and their prostaglandin-like hypotensive activity is demonstrated in the following test procedure. This procedure is a modification of the technique described by Pike, et al., Prostaglandins, Nobel Symposium 2, Stockholm, June, 1966, pg. 165.

Male Wistar strain rats (Royal Hart Farms) averaging approximately 250 g in weight are fastened to rat boards in a supine position by means of canvas vests and limb ties. The animals are anesthetized with a 900 mg/kg intraperitoneal dose of urethane. The left carotid artery is cannulated with polyethylene 50 tubing to measure arterial blood pressure and the left external jugular vein is cannulated with polyethylene 50 tubing for drug infusion. The animals are allowed to equilibrate for 15-30 minutes. The test compound is infused in 0.5 ml of saline, over a one minute period, at the indicated dose level, using a Harvard model 940 infusion pump and a 6 cc syringe at speed 5. Each drug dose is flushed with 0.4 ml of saline. The mean arterial blood pressure is measured before and after drug administration using a Statham model P23Db pressure transducer and a Brush model 260 recorder. The percent depression in mean arterial blood pressure and the duration of at least a 10% depression induced by representative compounds of this invention are recorded in Table C.

                                      TABLE C                                      __________________________________________________________________________     Hypotensive Activity                                                                                         Percent Depression                                                                       Duration in Minutes                                         Dose                                                                               No. of                                                                              of Mean Arterial                                                                         of at Least 10%                        Compound             mg/kg                                                                              Animals                                                                             Blood Pressure                                                                           Depression                             __________________________________________________________________________     nat(and ent)-9α,15-Dihydroxy-11-oxo-15,16-                               tetramethylene-17,18,19,29-tetranor-13-                                        trans-5-cis-prostadienoic acid                                                                      2.1 4    -29       >20                                    __________________________________________________________________________

The compounds of this invention are also useful as bronchodilators and accordingly have potential application in the treatment of asthma.

Bronchodilator activity is determined in guinea pigs against bronchospasms elicited by intravenous injections of 5-hydroxytryptamine, histamine or acetylcholine by the Konzett procedure. [See J. Lulling, P. Lievens, F. El Sayed and J. Prignot, Arzeneimittel-Forschung, 18, 995 (1968).] In Table D, bronchodilator activity for representative compounds of this invention against one or more of the three spasmogenic agents is expressed as an ED₅₀ determined from the results obtained with three logarithmic cumulative intravenous doses.

                                      TABLE D                                      __________________________________________________________________________     Bronchodilator Activity                                                                             ED.sub.50, mg/kg                                          Compound             5-Hydroxytryptamine                                                                       Histamine                                                                             Acetylcholine                           __________________________________________________________________________     nat(and ent-)9α,15-Dihydroxy-11-oxo-15,16-                               tetramethylene-17,18,19,20-tetranor-13-                                        trans,5-cis-prostadienoic acid                                                                      253 × 10.sup.-6                                                                     >3.2 × 10.sup.-3                                                                >3.2 × 10.sup.-3                  __________________________________________________________________________

The invention will be described in greater detail in conjunction with the following specific examples.

EXAMPLE 1 Preparation of trans-1-Hydroxy-2-(3-trifluoromethyl)phenoxycyclopentane

A mixture of 88 g of cyclopentene oxide, 150.7 g of 3-trifluoromethylphenol, 5.0 g of sodium hydroxide in 30 ml of water and 4.0 g of methyltricaprylyl ammonium chloride is stirred at 70°-80° C. for 51 hours and at 25° C. for 96 hours. The mixture is then diluted with methylene chloride and poured into water. The organic layer is washed with dilute sodium hydroxide solution and water. The solution is dried over magnesium sulfate. The solvent is removed giving 221.5 g of a liquid which is distilled (bp 110°-113° C. 0.8 mm) giving trans-1-hydroxy-2-(3-trifluoromethyl)phenoxycyclopentane.

EXAMPLE 2

In the manner described above in Example 1 from 4-fluorophenol and cyclopentane epoxide is prepared trans-1-hydroxy-2-(4-fluoro)phenoxycyclopentane.

EXAMPLE 3

In the manner described above in Example 1 from 3-chlorophenol and cyclopentane epoxide is prepared trans-1-hydroxy-2-(3-chloro)phenoxycyclopentane.

EXAMPLE 4 Preparation of 2-(3-Trifluoromethylphenoxy)cyclopentanone

To a suspension of 327.43 g of pyridinium chlorochromate in one liter of methylene chloride is added 220 g of trans-1-hydroxy-2-(3-trifluoromethylphenoxy)cyclopentane in 500 ml of methylene chloride. The mixture is stirred for 2 hours 15 minutes. Another 50 g of the oxidizing agent is added and the mixture is stirred for 41/2 hours. The mixture is diluted with ether and decanted from a black residue which is washed with more ether. The combined solutions are filtered through silica gel. The solvent is removed. The residue is dissolved in ether and again filtered through silica-gel. The solvent is removed and the residue is distilled (bp 113°-116° C., 1.5 mm) to give 188 g of 2-(3-trifluoromethylphenoxy)cyclopentanone.

EXAMPLE 5

In the manner described above for Example 4 is prepared from the product of Example 2; 2-(4-fluorophenoxy)cyclopentanone.

EXAMPLE 6

In the manner described above for Example 4 is prepared from the product of Example 3; 2-(3-chlorophenoxy)cyclopentanone.

EXAMPLE 7 Preparation of 1R,2S(and 1S,2R)-1-Ethynyl-1-hydroxy-2-butylcyclopentane and 1R,2R(and 1S,2S)-1-ethynyl-1-hydroxy-2-butylcyclopentane

Into 150 ml of dry tetrahydrofuran is bubbled purified acetylene, as a solution of 2.4 M n-butyl magnesium chloride (92 ml) is added dropwise with stirring over a 2 hour period. To the resulting solution of acetylene magnesium chloride is added 21 g of 2-butylcyclopentanone in 50 ml of tetrahydrofuran dropwise over 15 minutes. The solution is stirred for 30 minutes and then is poured into an ice cold solution of saturated ammonium chloride. The mixture is acidified to pH 5 and extracted with ether. The ether solution is washed with brine and dried over magnesium chloride. The ether is removed and the residue is distilled giving 14.8 g of a colorless liquid. This is chromatographed on a dry column of silica-gel eluting with benzene-ethyl acetate (19:1) to separate isomers giving 1R,2S(and 1S,2R)-1-ethynyl-1-hydroxy-2-butylcyclopentane and 1R,2R(and 1S,2S)-1-ethynyl-1-hydroxy-2-butylcyclopentane.

EXAMPLE 8 Preparation of 1-propargyl-1-hydroxycyclohexane

A stirred suspension of 121.6 g (5.0 mol) of magnesium in 1-1 of anhydrous ether is treated with 0.6 g of mercuric chloride and about 100 mg of iodine. After several minutes, 3 ml of propargyl bromide is added and if no exotherm is noted, a small amount of reacting propargyl bromide and magnesium in ether is added. When the reaction begins, a mixture of 5.0 mol of cyclohexanone and 595 g (5.0 mol) of propargyl bromide is added dropwise at a rate that produces vigorous refluxing of the solution. (The propargyl bromide must always be present in some excess otherwise the reaction will stop. If this happens, the addition of about 1 ml of propargyl bromide will restart the reaction). After about half of the propargy bromide-cyclohexanone mixture has been added, another 500-750 ml of ether is used to dilute the reaction mixture. At the end of the addition, the reaction mixture is refluxed for at least 0.5 hour, cooled and poured into 4 liters of saturated ammonium chloride during good stirring. The ethereal layer is separated and the aqueous layer is washed with ether several times and the combined extract is washed twice with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the ether yields 583 g (630 g theory) of a dark oil which is distilled giving purified 1-propargyl-1-hydroxycyclohexane.

EXAMPLES 9-26b

In the manner of Examples 7 and 8 described above the following acetylenic alcohols listed in Table I were prepared from the acetylenic Grignard reagent and ketone specified.

                                      Table I                                      __________________________________________________________________________     Example                                                                             Grignard Reagent                                                                        Ketone      Acetylenic Alcohol                                   __________________________________________________________________________      9   acetylene magne-                                                                        cyclohexanone                                                                              1-ethynyl-1-hydroxycyclohexane                            sium chloride                                                             10   acetylene magne-                                                                        cyclopentanone                                                                             1-ethynyl-1-hydroxycyclopentane                           sium chloride                                                             11   acetylene magne-                                                                        cycloheptanone                                                                             1-ethynyl-1-hydroxycycloheptane                           sium chloride                                                             12   acetylene magne-                                                                        3-propylcyclopentanone                                                                     1R,3S-(and 1S,3R-) 1-ethynyl-1-hydroxy-                   sium chloride        3-propylcyclopentane                                 13   acetylene magne-                                                                        3-propylcyclopentanone                                                                     1R,3R-(and 1S,3S-) 1-ethynyl-1-hydroxy-                   sium chloride        3-propylcyclopentane                                 14   acetylene magne-                                                                        2-butylcyclohexanone                                                                       1R,2S-(and 1S,2R-) 1-ethynyl-1-hydroxy-                   sium chloride        2-butylcyclohexane                                   15   acetylene magne-                                                                        2-butylcyclohexanone                                                                       1R,2R-(and 1S,2S-) 1-ethynyl-1-hydroxy-                   sium chloride        2-butylcyclohexane                                   16   acetylene magne-                                                                        2-(3-trifluoro-                                                                            1R,2S-(and 1S,2R-) 1-ethynyl-1-hydroxy-                   sium chloride                                                                           methylphenoxy)-                                                                            2-(3-trifluoromethylphenoxy)cyclopen-                              cyclopentanone                                                                             tane                                                 17   acetylene magne-                                                                        2-(3-trifluoro-                                                                            1R,2R-(and 1S,25-) 1-ethynyl-1-hydroxy-                   sium chloride                                                                           methylphenoxy)-                                                                            2-(3-trifluoromethylphenoxy)cyclopentane                           cyclopentanone                                                   18   acetylene magne-                                                                        2-(4-fluorophen-                                                                           1R,2S-(and 1S,2R-) 1-ethynyl-1-hydroxy-                   sium chloride                                                                           oxy)cyclopentanone                                                                         2-(4-fluorophenoxy)cyclopentane                      19   acetylene magne-                                                                        2-(4-fluorophen-                                                                           1R,2R-(and 1S,2S-) 1-ethynyl-1-hydroxy-                   sium chloride                                                                           oxy)cyclopentanone                                                                         2-(4-fluorophenoxy)cyclopentane                      20   acetylene magne-                                                                        2-(3-chlorophenoxy)-                                                                       1R,2S-(and 1S,2R-) 1-ethynyl-1-hydroxy-                   sium chloride                                                                           cyclopentanone                                                                             2-(3-chlorophenoxy)cyclopentane                      21   acetylene magne-                                                                        2-(3-chlorophenoxy)-                                                                       1R,2R-(and 1S,2S-) 1-ethynyl-1-hydroxy-                   sium chloride                                                                           cyclopentanone                                                                             2-(3-chlorophenoxy)cyclopentane                      22   acetylene magne-                                                                        3-methylcyclohexa-                                                                         1R,3S-(and 1S,3R-) 1-ethynyl-1-hydroxy-                   sium chloride                                                                           none        3-methylcyclohexane                                  23   acetylene magne-                                                                        3-methylcyclohexa-                                                                         1R,3R-(and 1S,3S-) 1-ethynyl-1-hydroxy-                   sium chloride                                                                           none        3-methylcyclohexane                                  24   propargyl magne-                                                                        2-butylcyclopenta-                                                                         1R,2S-(and 1S,2R-) 1-propargyl-1-hydroxy-                 sium bromide                                                                            none        2-butylcyclopentane                                  25   propargyl magne-                                                                        2-butylcyclopenta-                                                                         1R,2R-(and 1S,2S-) 1-propargyl-1-hydroxy-                 sium bromide                                                                            none        2-butylcyclopentane                                  26   propargyl magne-                                                                        2-(3-trifluoro-                                                                            1R,2S-(and 1S,2R-) 1-propargyl-1-hydroxy-                 sium bromide                                                                            methylphenoxy)-                                                                            2-(3-trifluoromethylphenoxy)cyclopentane                           cyclopentanone                                                   26b  propargyl magne-                                                                        2-(3-trifluoro-                                                                            1R,2R-(and 1S,2S)-1-propargyl-1-hydroxy-                  sium bromide                                                                            methylphenoxy)-                                                                            2-(3-trifluoromethylphenoxy)cyclopentane             __________________________________________________________________________

EXAMPLE 28a Preparation of 1R,2S(and 1S,2R)-1-Ethynyl-1-trimethylsilyloxy-2-butylcyclopentane

To a solution of 29.4 g of 1R,2S(and 1S,2R)-1-ethynyl-1-hydroxy-2-butylcyclopentane and 30.2 g of imidazole in 180 ml of dimethylformamide is added at 0° C. with stirring 24.1 g of trimethylsilylchloride. The mixture is stirred for 3 hours. The mixture is poured into 700 ml of hexane and washed twice with water and once with brine. The ether solution is dried over magnesium sulfate. The solvent is removed and the residue is distilled (bp 64°-72° C., 0.6 mm) to give 35.8 g of 1R,2S(and 1S,2R)-1-ethynyl-1-trimethylsilyloxy-2-butylcyclopentane.

EXAMPLE 28b Preparation of 1R,2R(and 1S,2S)-1-Ethynyl-1-trimethylsilyloxy-2-butylcyclopentane

To a mixture of 45.0 g of 1R,2R(and 1S,2S)-1-ethynyl-1-hydroxy-2-butylcyclopentane and 46.2 g of imidazole in 255 ml of dimethylformamide at 0° C. under nitrogen is added 36.9 of trimethylsilylchloride. The mixture is stirred at room temperature for 3 hours and then poured into 700 ml of hexane. Water is added, the organic layer is separated and the water layer is extracted with hexane. The combined hexane solutions are washed twice with water and dried over magnesium sulfate. The solvent is removed and the residue is distilled giving the product as 53 g of a colorless oil.

EXAMPLE 28c Preparation of 1-Ethynyl-1-trimethylsilyloxycyclohexane

A 194 g portion of imidazole and 158.2 g of 1-ethynylcyclohexan-1-ol are mixed with 500 g of dimethylformamide with cooling in an ice bath. A 152 g portion of trimethylchlorosilane is added with cooling and stirring in about one minute. The mixture is stirred for one hour and allowed to stand overnight. One liter of hexane is added. The lower layer is separated, diluted with water and extracted with hexane. The hexane layers are washed several times with water and then combined and dried over magnesium sulfate. Filtration and then evaporation of the hexane gives 198.5 g of product which is distilled giving 168 g of the desired product.

EXAMPLE 28d Preparation of 1-Propargyl-1-trimethylsilyloxycyclohexane

To a stirred solution of 55.4 g of 1-(2-propyn-1-yl)cyclohexanol [H. Gutmann, et al., Helv. Chim. Acta, 42, 719 (1959)] and 79 g of imidazole in 240 ml of DMF at 10° C. initially is added 56 ml of chlorodimethylsilane during 10 minutes. The cloudy yellow solution is stirred at room temperature for 26 hours. The resulting mixture is partitioned between 1000 ml of hexane and 400 ml of water at 0°-5° C. The hexane phase is washed successively with 6×200 ml of cold water and 200 ml of brine. The extract is dried over magnesium sulfate, filtered, and evaporated to give 85 g of colorless liquid, i.r. (film): 1240 and 830 cm⁻¹ (trimethylsilyloxy group).

EXAMPLE 29a Preparation of 1R,2S(and 1S,2R)-1-(trans-2-Iodovinyl)-1-trimethylsilyloxy-2-butylcyclopentane

To a mixture of 9.2 g of sodium borohydride and 45.8 of 2-methyl-2-butene in 350 ml of dry tetrahydrofuran at 0° C. with stirring under nitrogen is added, over 20 minutes, 41.1 ml of boron trifluoride etherate. After 3 hours, to this resulting solution of diisoamylborane is added 38.8 g of 1R,2S(and 1S,2R)-1-ethynyl-1-trimethylsilyloxy-2-butylcyclopentane in 40 ml of tetrahydrofuran in 20 minutes. The mixture is stirred 2 hours and then stored at -20° C. overnight. The mixture is allowed to warm to 0° C. and at 0° C. 85 g of dry trimethylamineoxide is added portionwise over 20 minutes. After stirring at 25° C. for one hour, the mixture is filtered through diatomaceous earth. The filtrate is poured simultaneously with a solution of 230 g of iodine in 250 ml of tetrahydrofuran into a stirred, cold solution of 430 g of sodium hydroxide in 1900 ml of water. After stirring for 30 minutes, the organic layer is separated. The aqueous layer is extracted with ether. The combined organic solutions are washed twice with a saturated solution of sodium thiosulfate and once with brine. The solution is dried over magnesium sulfate, the solvent is removed and the residue is dissolved in hexane. The hexane solution is filtered through diatomaceous earth and silica gel. The hexane is removed and the residue is purified by dry column chromatography on silica gel eluting with hexane: 45.35 g of 1R,2S(and 1S,2R)-1-(trans-2-iodovinyl)-1-trimethylsilyloxy-2-butylcyclopentane is obtained.

EXAMPLE 29b Preparation of 1R,2R(and 1S,2S)-1-(trans- 2-Iodovinyl)-1-trimethylsilyloxy-2-butylcyclopentane

To a mixture of 12.22 g of sodium borohydride and 60.82 g of 2-methyl-2-butene in 450 ml of tetrahydrofuran under nitrogen at 0° C., is added 54.6 ml of boron trifluoride etherate, dropwise over a 20 minute period. The solution is stirred at 0° C. for 2 hours and then at room temperature for 30 minutes. This solution is cooled to 0° C. and 55.5 g of 1R,2R(and 1S,2S)-1-ethynyl-1-trimethylsilyloxy-2-butylcyclopentane in 50 ml of tetrahydrofuran is added. The mixture is allowed to stand in a cold room overnight. To this mixture at 0° C. is added with stirring 112.8 g of trimethylamine oxide over a 20 minute period. The mixture is stirred at room temperature for 90 minutes and then filtered. To the filtrate is added simultaneously a solution of 565 g of sodium hydroxide in 2000 ml of water and a solution of 300 g of iodine in 300 ml of tetrahydrofuran. The mixture is stirred 30 minutes, the organic layer is separated and the aqueous layer is extracted with ether. The combined organic solutions are washed with saturated sodium thiosulfate solution and with saturated sodium chloride solution. The solution is dried with magnesium sulfate and filtered through a pad of silica gel. The solution is removed giving an orange liquid which is chromatographed on a dry column of silica gel giving 59.5 g of the product as a yellow liquid.

EXAMPLE 30 Preparation of 1-(3-Tri-n-butylstannyl-2-trans-propenyl)-1-trimethylsilyloxycyclohexane

To a stirred mixture of 31.5 g of 1-propargyl-1-trimethylsilyloxycyclohexane and 150 mg of azobisisobutyronitrile is added 41 ml of tri-n-butyltin hydride. The stirred mixture is heated to about 80° C. The initial exothermic reaction is moderated, and the temperature is subsequently maintained at 130°-135° C. for one hour.

The product is distilled to afford 56 g of colorless liquid, bp 150°-160° C. (0.15-0.3 mm), pmr (CDCl₃): 6.0 (multiplet, vinyl protons).

EXAMPLES 31-50

Using the procedure outlined above for Examples 28a, b, c and d, the acetylenic alcohols listed in Table II are converted to their corresponding acetylenic trimethylsilyloxy derivatives; these in turn using the procedure outlined above for Examples 29a and 29b, were converted to their corresponding trans-2-iodovinyl derivatives or using the procedure out above for Example 30, were converted to their corresponding trans-2-tri-n-butylstannyl derivatives (Table II).

                                      Table II                                     __________________________________________________________________________     Example                                                                             Acetylene of Example                                                                      Method of Example                                                                        Vinyl Iodide or Vinyl Tin Compound                   __________________________________________________________________________     31    9         29        1-(trans-2-iodovinyl)-1-trimethylsilyloxy-                                     cyclohexane                                          32   10         29        1-(trans-2-iodovinyl)-1-trimethylsilyloxy-                                     cyclopentane                                         33   11         30        1-(trans-2-tri-n-butylstannylvinyl)-1-tri-                                     methylsilyloxycycloheptane                           34   12         29        1R,3S-(and 1S,3R-) 1-(trans-2-iodovinyl)-1-                                    trimethylsilyloxy-3-propylcyclopentane               35   13         29        1R,3R-(and 1S,3S-) 1-(trans-2-iodovinyl)-1-                                    trimethylsilyloxy-3-propylcyclopentane               36    7         29        1R,2R-(and 1S,2S-) 1-(trans-2-iodovinyl)-1-                                    trimethylsilyloxy-2-butylcyclopentane                37   14         29        1R,2S-(and 1S,2R-) 1-(trans-2-iodovinyl)-1-                                    trimethylsilyloxy-2-butylcyclohexane                 38   15         29        1R,2R-(and 1S,2S-) 1-(trans-2-iodovinyl)-1-                                    trimethylsilyloxy-2-butylcyclohexane                 39   16         30        1R,2S-(and 1S,2R-) 1-(trans-2-tri-n-butyl-                                     stannylvinyl)-1-trimethylsilyloxy-2-(3-                                        trifluoromethylphenoxy)cyclopentane                  40   17         30        1R,2R-(and 1S,2S-) 1-(trans-2-tri-n-butyl-                                     stannylvinyl)-1-trimethylsilyloxy-2-(3-tri-                                    fluoromethylphenoxy)cyclopentane                     41   18         29        1R,2S-(and 1S,2R-) 1-(trans-2-iodovinyl)-                                      1-trimethylsilyloxy-2-(4-fluorophenoxy)-                                       cyclopentane                                         42   19         29        1R,2R-(and 1S,2S-) 1-(trans-2-iodovinyl)-                                      1-trimethylsilyloxy-2-(4-fluorophenoxy)-                                       cyclopentane                                         43   20         30        1R,2S-(and 1S,2R-) 1-(trans-2-tri-n-butyl-                                     stannylvinyl)-1-trimethylsilyloxy-2-(3-                                        chlorophenoxy)cyclopentane                           44   21         30        1R,2R-(and 1S,2S-) 1-(trans-2-tri-n-butyl-                                     stannylvinyl)-1-trimethylsilyloxy-2-(3-                                        chlorophenoxy)cyclopentane                           45   22         29        1R,3S-(and 1S,3R-) 1-(trans-2-iodovinyl)-1-                                    trimethylsilyloxy-3-methylcyclohexane                46   23         29        1R,3R-(and 1S,3S-) 1-(trans-2-iodovinyl)-1-                                    trimethylsilyloxy-3-methylcyclohexane                47   24         30        1R,2S-(and 1S,2R-) 1-(3-tri-n-butylstannyl-                                    2-trans-propenyl)-1-trimethylsilyloxy-2-                                       butylcyclopentane                                    48   25         30        1R,2R-(and 1S,2S-) 1-(3-tri-n-butylstannyl-                                    2-trans-propenyl)-1-trimethylsilyloxy-2-                                       butylcyclopentane                                    49   26         30        1R,2S-(and 1S,2R-) 1-(3-tri-n-butylstannyl-                                    2-trans-propenyl)-1-trimethylsilyloxy-2-                                       (3-trimfluoromethylphenoxy)cyclopentane              50   27         30        1R,2R-(and 1S,2S-) 1-(3-tri-n-butylstannyl-                                    2-trans-propenyl)-1-trimethylsilyloxy-2-                                       (3-trifluoromethylpenoxy)cyclopentane                __________________________________________________________________________

EXAMPLE 51 Preparation of 2-(6-Carbotrimethylsilyloxyhex-2-cis-enyl)-4-trimethylsilyloxycyclopent-2-en-1-one

To a solution of one g of 2-(6-carboxyhex-2-cis-enyl)-4-hydroxycyclopent-2-en-1-one in 12.5 ml of dry pyridine at 15° C. under argon is added with stirring 3.3 ml of hexamethyldisilazane (HMDS) followed by dropwise addition of 1.6 ml of trimethylchlorosilane (TMCS). The resulting mixture is stirred at ambient temperature for one hour then taken to dryness (vac. pump). The residue is taken up in hexanes and filtered thru Celite. Evaporation of the mother liquor followed by two evaporations with toluene furnished 1.5 g (96%) of pure 2-(6-carbotrimethylsilyloxyhex-2-cis-enyl)-4-trimethylsilyloxycyclopent-2-en-1-one.

EXAMPLE 52 Preparation of 2-(6-Carbotrimethylsilyloxyhexyl)-4-trimethylsilyloxycyclopent-2-en-1-one

To a solution of one g of 2-(6-carboxyhexyl)-4-hydroxycyclopent-2-en-1-one in 12.5 ml of dry pyridine at 15° C. under argon, is added with stirring 3.3 ml of hexamethyldisilazane followed by dropwise addition of 1.6 ml of trimethylchlorosilane. The resulting mixture is stirred at ambient temperature for one hour and then taken to dryness. The residue is taken up in hexane and filtered through diatomaceous earth. Evaporation of the mother liquor followed by two evaporations with toluene gives pure product.

EXAMPLE 53 Preparation of 2-(6-carbomethoxyhexyl)-4(R)-trimethylsilyloxycyclopent-2-en-1-one

To a solution of 1.0 g of 2-(6-carbomethylhexyl)-4(R)-hydroxycyclopent-2-en-1-one [R. Pappo, et al., Tetrahedron Letters, 943 (1973)] in 12.5 ml of dry pyridine at 15° under argon was added with stirring 3.3 ml (24 mmoles) of hexamethyldisilazane (HMDS) followed by dropwise addition of 1.6 ml (20.5 mmoles) of trimethylchlorosilane (TMCS). The resulting mixture was stirred at ambient temperature for 1 hour then taken to dryness (vac. pump). The residue is taken up in hexanes and filtered thru Celite. Evaporation of the mother liquor followed by two evaporations with toluene furnished 2-(6-carbomethoxyhexyl)-4(R)-trimethylsilyloxycyclopent-2-en-1-one.

EXAMPLE 54 Preparation of 2-(6-carbomethoxyhexyl)-4(S)-trimethylsilyloxycyclopent-2-en-1-one

In the manner described in Example 239, treatment of 2-(6-carbomethoxyhexyl)-4(S)-hydroxycyclopent-2-en-1-one [R. Pappo, et al., Tetrahedron Letters, 943 (1973)] with hexamethyldisilazane and trimethylsilylchloride gives the subject product.

EXAMPLE 55 Preparation of 5-chloro-1-(2-furyl)-1-pentanol

To a stirred suspension of 2-furyllithium (prepared from 0.53 moles of n-butyllithium and 39.5 g of furan by the procedure of J. Org. Chem., 27, 1216 (1962)) in 350 ml of ether and ca. 200 ml of hexane at -78° is added a solution of 57.9 g of 5-chloropentanol (Chem. Abstr. 59, 7579F (1963)) in 80 ml of ether during 25 minutes. The mixture is warmed to 0° during 20 minutes, stirred at 0° for 15 minutes, and treated with 140 ml of saturated ammonium chloride. The ether phase is washed with water and brine, dried over magnesium sulfate and potassium carbonate mixture, and concentrated to give a liquid, pmr spectrum (CDCl₃): δ 3.59 (triplet, CH₂ Cl₂) and 4.70 (triplet, CH₂ CHOH).

EXAMPLE 56 Preparation of 5-(carbethoxymethylthio)-1-(2-furyl)-1-pentanol

To a stirred, refluxing mixture of 76 g of ethyl mercaptoacetate, 79.5 g of 5-chloro-1-(2-furyl)-1-pentanol (Example 55), and 10 ml of 1.5 M sodium ethoxide in ethanol is added an additionan 300 ml of 1.5 M sodium ethoxide during 15 minutes. The resulting mixture is stirred at reflux for 3 hours, cooled, and concentrated to remove most of the ethanol. The residue is partitioned with ether and water. The ether phase is washed with brine and dried over potassium carbonate. The solution is concentrated, diluted with xylene, and again concentrated to give an oil, pmr spectrum (CDCl₃): δ 3.24 (singlet, --S--CH₂ CO₂ C₂ H₅) and 4.70 (triplet, CH₂ CHOH).

EXAMPLE 57 Preparation of 2-(6-carboxy-5-thiahexyl)-4-hydroxycyclopent-2-en-1-one

A stirred solution of 125 g of 5-(carbethoxymethylthio)-1-(2-furyl)-1-pentanol (Example 56), 22.4 g of sodium formate, 250 ml of formic acid, and 400 mg of hydroquinone in 2000 ml of dioxane and 1330 ml of water is refluxed for 20 hours.

The solution, containing crude 3-hydroxy-2-[4-(carbethoxymethylthio)butyl]cyclopent-4-en-1-one, is cooled and treated during 10 minutes with 75 ml of sulfuric acid (d=1.84) with stirring. The stirred solution is refluxed for 16 hours, cooled, saturated with sodium chloride, and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, and concentrated. The residue is subjected to chromatography on silica gel with chloroform progressively enriched in ether, ether, and ether progressively enriched in acetone to afford the subject compound as an oil, pmr spectrum (CDCl₃)- δ 3.24 (singlet, --S--CH₂ --CO₂ C₂ H₅), 5.0 (broad singlet --CHOH--).

EXAMPLE 58 Preparation of 2-(6-carbotrimethylsilyloxy-5-thiahexyl)-4-trimethylsiloxycyclopent-2-en-1-one

To a stirred solution of 28.4 g of 4-hydroxy-2-[4-(carboxymethylthio)butyl]cyclopent-2-en-1-one and 76 ml of hexamethyldisilazane in 330 ml of pyridine at 5° is added 38 ml of chlorotrimethylsilane during 5 minutes. The mixture is stirred at ambient temperature for 3.5 hours, at 45° for 5 minutes, and then evaporated to remove solvent. The residue is stirred with 1000 ml of petroleum ether and filtered. The filtrate is treated with charcoal and filtered; this filtrate is concentrated with the aid of toluene to give a liquid, pmr spectrum (CDCl₃): δ 0.18 (singlet, trimethylsiloxy group) and 0.28 (singlet, trimethylsiloxycarbonyl group).

EXAMPLE 59 Preparation of 4-chloro-1-(2-furyl)-1-butanol

To a stirred suspension of 2-furyllithium (prepared from 0.53 moles of n-butyllithium and 39.5 g of furan by the procedure of J. Org. Chem., 27, 1216 (1962)) in 350 ml of ether and ca. 200 ml of hexane at -78° is added a solution of 57.9 g of 4-chlorobutanol (Chem. Abstr., 59, 7579F (1963)) in 80 ml of ether during 25 minutes. The mixture is warmed to 0° during 20 minutes, stirred at 0° for 15 minutes, and treated with 140 ml of saturated ammonium chloride. The ether phase is washed with water and brine, dried over magnesium sulfate and potassium carbonate mixture, and concentrated to give a liquid, pmr spectrum (CDCl₃): δ 3.59 (triplet, CH₂ Cl) and 4.70 (triplet, CH₂ CHOH).

EXAMPLE 60 Preparation of 4-carbethoxymethylthio)-1-(2-furyl)-1-butanol

To a stirred, refluxing mixture of 76 g of ethyl mercaptoacetate, 79.5 g of 4-chloro-1-(2-furyl)-1-butanol (Example 59), and 10 ml of 1.5 M sodium ethoxide in ethanol is added an additional 300 ml of 1.5 M sodium ethoxide during 15 minutes. The resulting mixture is stirred at reflux for 3 hours, cooled, and concentrated to remove most of the ethanol. The residue is partitioned with ether and water. The ether phase is washed with brine and dried over potassium carbonate. The solution is concentrated, diluted with xylene, and again concentrated to give an oil, pmr spectrum (CDCl₃): δ 3.24 (singlet, --S--CH₂ --CO₂ C₂ H₅) and 4.70 (triplet, CH₂ CHOH).

EXAMPLE 61 Preparation of 2-(5-carboxy-4-thiapentyl)-4-hydroxycyclopent-2-en-1-one

A stirred solution of 125 g of 4-(carbethoxymethylthio)-1-(2-furyl)-1-butanol (Example 60), 22.4 g of sodium formate, 250 ml of formic acid, and 400 mg of hydroquinone in 2000 ml of dioxane and 1330 ml of water is refluxed for 20 hours.

The solution, containing crude 3-hydroxy-2-[3-(carbethoxymethylthio)propyl]cyclopent-4-en-1-one, is cooled and treated during 10 minutes with 75 ml of sulfuric acid (d=1.84) with stirring. The stirred solution is refluxed for 16 hours, cooled, saturated with sodium chloride, and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, and concentrated. The residue is subjected to chromatography on silica gel with chloroform progessively enriched in ether, ether, and other progressively enriched in acetone to afford the subject compound as an oil.

EXAMPLE 62 Preparation of 2-(5-carbotrimethylsilyloxy-4-thiapentyl)-4-trimethylsiloxycyclopent-2-en-1-one

To a stirred solution of 28.4 g of 4-hydroxy-2-[4-(carboxymethylthio)butyl]cyclopent-2-en-1-one and 76 ml of hexamethyldisilazane in 330 ml of pyridine at 5° is added 38 ml of chlorotrimethylsilane during 5 minutes. the mixture is stirred at ambient temperature for 3.5 hours, at 45° for 5 minutes, and then evaporated to remove solvent. The residue is slurried with 1000 ml of petroleum ether and filtered. The filtrate is treated with charcoal and filtered; this filtrate is concentrated with the aid of toluene to give a liquid, pmr spectrum (CDCl₃): δ 0.18 (singlet, trimethylsiloxy group) and 0.28 (singlet, trimethylsiloxycarbonyl group).

EXAMPLE 63 Preparation of nat(and ent)-11α,15-dihydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor prostanoic acid

A solution of nat(and ent)-11α,15-dihydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-13-trans-prostanoic acid (800 mg) in 50 ml of ethyl acetate is hydrogenated in a Parr apparatus using 500 mg of 5% rhodium-on-carbon. The catalyst is removed by filtration and the filtrate is taken to dryness to furnish of the titled product.

EXAMPLES 64-66

Hydrogenation of the prostenoic acids listed in Table XI below in ethyl acetate using a rhodium-on-carbon catalyst in accordance with the method described in Example 63 gives the prostanoic acids of the table.

                                      Table III                                    __________________________________________________________________________          13-trans-prostenoic acid                                                  Example                                                                             of Example  Prostanoic Acid                                               __________________________________________________________________________     64   72          nat-15S,16R-(and ent-15R,16S)-11α,15-dihydroxy-                          9-oxo-15,16-trimethylene prostanoic acid                      65   73          nat-15S,16S-(and ent-15R,16R)-11α,15-dihydroxy-                          9-oxo-15,16-trimethylene prostanoic acid                      66   83          nat-(and ent)-11α,16-dihydroxy-9-oxo-16,17-tetra-                        methylene-18,19,20-trinor prostanoic acid                     __________________________________________________________________________

EXAMPLE 67 Preparation of nat(and ent)-11α,15-Dihydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-5-cis,13-trans-prostadienoic Acid

A 6.48 ml solution of 2.3 M n-butyllithium in hexane is added, at 0° C. under nitrogen, to a solution of 1.64 g of thiophenol in 45 ml of ether. After one hour at 0° C. a solution of 5.85 g of tri-n-butylphosphine-copper complex in 140 ml of ether is added and the mixture is stored in a freezer overnight. To a solution of 4.54 g of 1-(trans-2-iodo-vinyl)-1-trimethylsilyloxycyclohexane in 8 ml of toluene at -40° C. under nitrogen is added, with stirring, 35 ml of a solution of t-butyllithium. After 90 minutes a few ml of ether is added and the mixture is stirred at room temperature for 15 minutes. This solution is recooled to -78° C. and the copper solution is cooled to -78° C. and transferred to the vinyl lithium solution in a steady stream. The solution is stirred at -78° C. for 35 minutes and a solution of 5.0 g of 2-(6-carbotrimethylsilyloxyhex-2-cis-enyl)-4-trimethylsilyloxycyclopent-2-en-1-one (Ex. 51) in 10 ml of ether is added. The mixture is placed in bath at -45° C., stirred for 3 hours and allowed to warm to -20° C. over 15 minutes. A solution of 2.0 g of acetic acid in 5 ml of ether is added after recooling to -40° C. Saturated NH₄ Cl solution is added followed by a small amount of dilute HCl. The mixture is poured into ether. The aqueous layer is extracted with ether. The combined ether solutions are washed with dilute HCl, twice with water and then with saturated NaCl. The ether is dried over MgSO₄ and the solvent is removed giving a yellow oil. This is stirred in 50 ml of acetic acid:tetrahydrofuran:water (4:2:1) for 45 minutes and then poured into water. The solution is extracted with ether and the ether solution is washed with water twice and once with brine. The solution is dried over magnesium sulfate and the solvent is removed. The residue is chromatographed on a dry column of silica gel eluting with ethyl acetate containing 1% acetic acid to give 2.15 g of nat(and ent)-11α,15-dihydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-5-cis,13-trans-prostadienoic acid.

EXAMPLE 68 Preparation of nat(and ent)-11α,15-Dihydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-13-trans-prostenoic Acid

To a solution of 1.01 g of thiophenol in 30 ml of ether under nitrogen at 0° C., is added with stirring, 4.0 ml of 2.3 M n-butyllithium. The mixture is stirred for one hour and then a solution of 3.61 g of copper tri-n-butyl phosphine complex in 85 ml of ether is added.

To 2.98 g of 1-(2-trans-iodovinyl)-1-trimethylsilyloxycyclohexane in 8 ml of toluene at -45° C., under nitrogen, is added with stirring 23 ml of 0.8 M t-butyllithium. Stirring and cooling are continued for 75 minutes. The cooling bath is removed and the solution is stirred for 10 minutes. A 5 ml portion of ether is added and the solution is cooled to -78° C. The copper solution is cooled to -78° C. and then added to the vinyl lithium solution via a double needle. After 30 minutes, a solution of 3.4 g of 1-(6-carbotrimethylsilyloxyhexyl)-4-trimethylsilyloxycyclopent-2-en-1-one in ether is added. The solution is then placed in a dry ice-acetonitrile bath at -45° C. to -50° C. and stirred for 3 hours. The solution is allowed to warm to -20° C. over 20 minutes and stirred at -20° C. for 10 minutes. To this solution is added 5 ml of acetic acid in 5 ml of ether followed by 0.5 M hydrochloric acid. The solution is poured into water and extracted with ether. The ether solution is washed with water and dried with magnesium sulfate. The solvent is removed followed by removal of most of the thiophenol. The residue is dissolved in 100 ml of a mixture of acetic acid, tetrahydrofuran and water and stirred for one hour. The mixture is poured into water and extracted with ether. The ether extract is washed several times with water and dried with magnesium sulfate. The ether is removed leaving a yellow oil. This oil is chromatographed on a dry silica gel column eluting with ether:ethyl acetate 1:1. The product is isolated as a light green-yellow oil which solidifies on drying to give an off-white solid.

EXAMPLE 69 Preparation of nat(and ent)-11α,16-Dihydroxy-9-oxo-16,17-tetramethylene-18,19,20-trinor-5-cis,13-trans-prostadienoic Acid

A solution of 10.3 g of 1-(3-tri-n-butylstannyl-2-trans-propenyl)-1-trimethylsilyloxycyclohexane (Ex. 30) in 7 ml of tetrahydrofuran is cooled in a dry ice-acetone bath under nitrogen and treated with 8.6 ml of 2.5M n-butyllithium in hexane during 10 minutes. The resulting solution is stirred at -40° C. for one hour, then at -20° C. to -30° C. for another hour, recooled to -78° C., and treated during 10 minutes with the solution of 2.68 g of copper pentyne, 7.87 ml of hexamethylphosphorus triamide and 19 ml of tetrahydrofuran. The resulting solution is stirred at -70° C. to -50° C. for one hour, recooled to -78° C., and treated with a solution of 5.8 g of 2-(6-carbotrimethylsilyloxyhex-2-cis-enyl)-4-trimethylsilyloxycyclopent-2-en-1-one (Ex. 51) in 12 ml of tetrahydrofuran during 10 minutes. The mixture is then stirred at -40° C. to -50° C. for 40 minutes, then at -20° C. to -25° C. for 25 minutes, recooled to -40° C., and poured into 500 ml of cold, saturated ammonium chloride solution and 300 ml of ether. To the resulting mixture is added 8 ml of glacial acetic acid and it is extracted with ether. The combined ether extract is washed with water, diluted hydrochloric acid, filtered through Celite and washed again with water and saturated sodium chloride solution. Evaporation of the solvents at reduced pressure gives 15.2 g of oil. A solution of this crude oil in 175 ml of glacial acetic acid:tetrahydrofuran:water (4:2:1) is stirred at room temperature under nitrogen for 50 minutes. To the mixture is added 150 ml of toluene and concentrated at reduced pressure. The crude product obtained is purified by chromatography on silica gel to give nat(and ent)-11α,16-dihydroxy-9-oxo-16,17-tetramethylene-18,19,20-trinor-5-cis,-13-trans-prostadienoic acid.

EXAMPLE 70 Preparation of nat-15S,16R(and ent-15R,16S) and nat-15R,16S-(and ent-15S,16R)-11α,15-Dihydroxy-9-oxo-15,16-trimethylene-13-trans-5-cis-prostadienoic Acid

To a solution of 1.44 g of thiophenol in 40 ml of ether under nitrogen at 0° C. is added with stirring, 5.65 ml of 2.3M n-butyllithium. After one hour of stirring at 0° C. a solution of bis-tri-n-butylphosphine copper iodide complex in 100 ml of ether is added and the solution is stored overnight in a freezer.

To 4.76 g of 1R,2S(and 1S,2R)-1-(trans-2-iodovinyl)-1-trimethylsilyloxy-2-butylcyclopentone in 10 ml of toluene under nitrogen at -45° C., is added with stirring, 32.5 ml of of 0.8M t-butyllithium. After stirring for 90 minutes at -45° C. the solution is removed from the cooling bath and stirred 15 minutes. The solution is cooled to -78° C. The copper solution is cooled to -78° C. and then added to the vinyl lithium solution. After 30 minutes a solution of 4.4 g of 1-(6-carbotrimethylsilyloxyhex-2-cis-enyl)-4-trimethylsilyoxycyclopent-2-en-1-one in 20 ml of ether is added. The solution is stirred at -45° C. for 3 hours and then allowed to warm to -20° C. over a 30 minute period. The solution is stirred at -20° C. for 15 minutes and then a solution of 2.5 ml of acetic acid in 15 ml of ether is added followed by dilute hydrochloric acid. The mixture is extracted with ether. The ether extract is washed with saturated sodium chloride solution and dried with magnesium sulfate. The solvent is removed giving a yellow oil. This oil is stirred in 70 ml of acetic acid:tetrahydrofuran:water (4:2:1) for one hour, poured into water and extracted with ether. The extract is dried with magnesium sulfate and the ether is removed. The residue is chromatographed on a dry column of silica gel, eluting with ether to give the separated isomers.

EXAMPLES 72-145

In the manner described hereinabove for Examples 67-70, the 9-oxo-prostaglandins shown in Table III are prepared from the indicated vinyl iodide or vinyl tin compounds and the indicated cyclopent-2-en-1-one. In the reactions involving the 4-hydroxycyclopent-2-en-1-ones, these were first converted to their corresponding bis-trimethylsilyloxy derivatives as described hereinabove for Examples 51 and 52. Only the acids are listed in Table III and it is to be understood that both the acid and esters are claimed in this invention. In those cases where two diastereoisomers are formed in the conjugate-addition, only one of the diastereoisomers is listed in Table III. It should be understood that the other diastereoisomer is also formed which in its nat and ent forms has an opposite (mirror image) configuration at the assymmetric carbon atoms on the -chain (the chain containing C₁₃ . . . C₁₄ etc.) to that of the respective nat and ent forms of the listed diastereoisomer; both of these diastereoisomers are claimed in this invention as well as their component enantiomers.

                                      Table IV                                     __________________________________________________________________________                                   Product 9-oxo-prostaglandin and its                   Vinyl Iodide or Vinyl    diastereoisomer and ethyl ester                  Example                                                                             Tin of Example                                                                            Cyclopent-2-en-1-one                                                                         where applicable (see hereinabove)               __________________________________________________________________________     72    29a        2-(6-carboxyhexyl)-4-hy-                                                                    nat-15S,16R-(and ent-15R,16S)-11α-                         droxycyclopent-2-en-1-one                                                                    15-dihydroxy-9-oxo-15,16-trimethyl-                                            lene-13-trans-prostenoic acid                    73   36         2-(6-carboxyhexyl)-4-hy-                                                                     nat-15S,16S-(and ent-15R,16R)-11α-                         droxycyclopent-2-en-1-one                                                                    15-dihydroxy-9-oxo-15,16-trimethy-                                             lene-13-trans-prostenoic acid                    74   31         2-(6-carboxyhexyl)-4-hy-                                                                     nat-(and ent)-11α,15-dihydroxy-9-                          droxycyclopent-2-en-1-one                                                                    oxo-15,16-tetramethylene-17,18,19,-                                            20-tetranor-13-trans-prostenoic acid             75   32         2-(6-carboxyhexyl)-4-hy-                                                                     nat-(and ent)-11α,15-dihydroxy-9-                          droxycyclopent-2-en-1-one                                                                    oxo-15,16-trimethylene-17,18,19,20-                                            tetranor-13-trans-prostenoic acid                76   33         2-(6-carboxyhexyl)-4-hy-                                                                     nat-(and ent)-11α,15-dihydroxy-15,-                        droxycyclopent-2-en-1-one                                                                    16-pentamethylene-17,18,19,20-tetra-                                           nor-13-trans-prostenoic acid                     77   34         2-(6-carboxyhexyl)-4-hy-                                                                     nat-15S,17R-(and ent-15R,17S)-11α-                         droxycyclopent-2-en-1-one                                                                    15-dihydroxy-9-oxo-15,17-dimethyl-                                             lene-13-trans-prostenoic acid                    78   35         2-(6-carboxyhexyl)-4-hy-                                                                     nat-15S,17S-(and ent-15R,17R)-11α-                         droxycyclopent-2-en-1-one                                                                    15-dihydroxy-9-oxo-15,17-dimethy-                                              lene-13-trans-prostenoic acid                    79   37         2-(6-carboxyhexyl)-4-hy-                                                                     nat-15S,16R-(and ent-15R,16S)-11α-                         droxycyclopent-2-en-1-one                                                                    15-dihydroxy-9-oxo-15,16-tetra-                                                methylene-13-trans-prostenoic acid               80   38         2-(6-carboxyhexyl)-4-hy-                                                                     nat-15S,16S-(and ent-15R,16R)-11α-                         droxycyclopent-2-en-1-one                                                                    15-dihydroxy-9-oxo-15,16-tetra-                                                methylene-13-trans-prostenoic acid               81   39         2-(6-carboxyhexyl)-4-hy-                                                                     nat-15R,16S-(and ent-15S,16R)-11α-                         droxycyclopent-2-en-1-one                                                                    15-dihydroxy-9-oxo-15,16-trimethyl-                                            lene-16-(3-trifluoromethylphenoxy)-                                            17,18,19,20-tetranor-13-trans-                                                 prostenoic acid                                  82   40         2-(6-carboxyhexyl)-4-hy-                                                                     nat-15R,16R-(and ent-15S,16S)-11α,-                        droxycyclopent-2-en-1-one                                                                    15-dihydroxy-9-oxo-15,16-trimethy-                                             lene-16-(3-trifluoromethylphenoxy)-                                            17,18,19,20-tetranor-13-trans-                                                 prostenoic acid                                  83   30         2-(6-carboxyhexyl)-4-hy-                                                                     nat-(and ent)-11α,16-dihydroxy-9-                          droxycyclopent-2-en-1-one                                                                    oxo-16,17-tetramethylene-18,19,20-                                             trinor-13-trans-prostenoic acid                  84   41         2-(6-carboxyhexyl)-4-hy-                                                                     nat-15R,16S-(and ent-15S,16R)-11α,-                        droxycyclopent-2-en-1-one                                                                    15-dihydroxy-9-oxo-15,16-trimethy-                                             lene-16-(4-fluorophenoxy)-17,18,19,-                                           20-tetranor-13-trans-prostenoic acid             85   42         2-(6-carboxyhexyl)-4-hy-                                                                     nat-15R,16R-(and ent-15S,16S)-11α-                         droxycyclopent-2-en-1-one                                                                    15-dihydroxy-9-oxo-15,16-trimethy-                                             lene-16-(4-fluorophenoxy)-17,18,19,-                                           20-tetranor-13-trans-prostenoic acid             86   43         2-(6-carboxyhexyl)-4-hy-                                                                     nat-15R,16S-(and ent-15S,16R)-11α-                         droxycyclopent-2-en-1-one                                                                    15-dihydroxy-9-oxo-15,16-trimethyl-                                            lene-16-(3-chlorophenoxy)-17,18,19,-                                           20-tetranor-13-trans-prostenoic acid             87   44         2-(6-carboxyhexyl)-4-hy-                                                                     nat-15R,16R-(and ent-15S,16S)-11α-                         droxycyclopent-2-en-1-one                                                                    15-ihydroxy-9-oxo-15,16-trimethy-                                              lene-16-(3-chlorophenoxy)-17,18,19,-                                           20-tetranor-13-trans-prostenoic acid             88   45         2-(6-carboxyhexyl)-4-hy-                                                                     nat-15S,17R-(and ent-15R,17S)-11α-                         droxycyclopent-2-en-1-one                                                                    15-dihydroxy-9-oxo-15,17-trimethy-                                             lene-19,20-dinor-13-trans-prostenoic                                           acid                                             89   46         2-(6-carboxyhexyl)-4-hy-                                                                     nat-15S,17S-(and ent-15R,17R)-11α-                         droxycyclopent-2-en-1-one                                                                    15-dihydroxy-9-oxo-15,17-trimethy-                                             lene-19,20-dinor-13-trans-prostenoic                                           acid                                             90   47         2-(6-carboxyhexyl)-4-hy-                                                                     nat-16R,17S-(and ent-16S,17R)-11α-                         droxycyclopent-2-en-1-one                                                                    16-dihydroxy-9-oxo-16,17-trimethy-                                             lene-20-methyl-13-trans-prostenoic                                             acid                                             91   48         2-(6-carboxyhexyl)-4-hy-                                                                     nat-16R,17R-(and ent-16S,17S)-11α-                         droxycyclopent-2-en-1-one                                                                    16-dihydroxy-9-oxo-16,17-trimethy-                                             lene-20-methyl-13-trans-prostenoic                                             acid                                             92   49         2-(6-carboxyhexyl)-4-hy-                                                                     nat-16R,17S-(and ent-16S,17R)-11α-                         droxycyclopent-2-en-1-one                                                                    16-dihydroxy-9-oxo-16,17-trimethy-                                             lene-16-(3-trifluoromethylphenoxy)-                                            18,19,20-trinor-13-trans-prostenoic                                            acid                                             93   50         2-(6-carboxyhexyl)-4-hy-                                                                     nat-16R,17R-(and ent-16S,17S)-11α-                         droxycyclopent-2-en-1-one                                                                    16-dihydroxy-9-oxo-16,17-trimethy-                                             lene-16-(3-trifluoromethylphenoxy)-                                            18,19,20-trinor-13-trans-prostenoic                                            acid                                             94    29a       2-(5-carboxypentyl)-4-hy-                                                                    nat-15S,16R-(and ent-15R,16S)-11α-                         droxycyclopent-2-en-1-one                                                                    15-dihydroxy-9-oxo-15,16-trimethy-                                             lene-7-nor-13-trans-prostenoic acid              95   36         2-(5-carboxypentyl)-4-hy-                                                                    nat-15S,16S-(and ent-15R,16R)-11α-                         droxycyclopent-2-en-1-one                                                                    15-dihydroxy-9-oxo-15,16-trimethy-                                             lene-2-nor-13-trans-prostenoic acid              96   31         2-(5-carboxypentyl)-4-hy-                                                                    nat-(and ent)-11α,15-dihydroxy-9-                          droxycyclopent-2-en-1-one                                                                    oxo-15,16-tetramethylene-2,17,18-                                              19,20-pentanor-13-trans-prostenoic                                             acid                                             97   32         2-(5-carboxypentyl)-4-hy-                                                                    nat-(and ent)-11α,15-dihydroxy-9-                          droxycyclopent-2-en-1-one                                                                    oxo-15,16-trimethylene-2,17,18-                                                19,20-pentanor-13-trans-prostenoic                                             acid                                             98   33         2-(5-carboxypentyl)-4-hy-                                                                    nat-(and ent)-11α,15-dihydroxy-9-                          droxycyclopent-2-en-1-one                                                                    oxo-15,16-pentamethylene-2,17,18-                                              19,20-pentanor-13-trans-prostenoic                                             acid                                             99   34         2-(5-carboxypentyl)-4-hy-                                                                    nat-15S,17R-(and ent-15R,17S)-11α,-                        droxycyclopent-2-en-1-one                                                                    15-dihydroxy-9-oxo-15,17-dimethy-                                              lene-2-nor-13-trans-prostenoic acid              100  35         2-(5-carboxypentyl)-4-hy-                                                                    nat-15S,17S-(and ent-15R,17R)-11α-                         droxycyclopent-2-en-1-one                                                                    15-dihydroxy-9-oxo-15,17-dimethy-                                              lene-2-nor-13-trans-prostenoic acid              101  39         2-(5-carboxypentyl)-4-hy-                                                                    nat-15R,16S-(and ent-15S,16R)-11α-                         droxycyclopent-2-en-1-one                                                                    15-dihydroxy-9-oxo-15,16-trimethy-                                             lene-16-(3-trifluoromethylphenoxy)-                                            2,17,18,19,20-pentanor-13-trans-                                               prostenoic acid                                  102  40         2-(5-carboxypentyl)-4-hy-                                                                    nat-15R,16R-(and ent-15S,16S)-11α-                         droxycyclopent-2-en-1-one                                                                    15-dihydroxy-9-oxo-15,16-trimethy-                                             lene-16-(3-trifluoromethylphenoxy)-                                            2,17,18,19,20-pentanor-13-trans-                                               prostenoic acid                                  103   29a       2-(7-carboxyheptyl)-4-hy-                                                                    nat-15S,16R-(and ent-15R,16S)-11α-                         droxycyclopent-2-en-1-one                                                                    15-dihydroxy-9-oxo-15,16-trimethy-                                             lene-1-homo-13-trans-prostenoic acid             104  36         2-(7-carboxyheptyl)-4-hy-                                                                    nat-15S,16S-(and ent-15R,16R)-11α,-                        droxycyclopent-2-en-1-one                                                                    15-dihydroxy-9-oxo-15,16-trimethy-                                             lene-1-homo-13-trans-prostenoic acid             105  31         2-(7-carboxyheptyl)-4-hy-                                                                    nat-(and ent)-11α,15-dihydroxy-9-                          droxycyclopent-2-en-1-one                                                                    oxo-15,16-tetramethylene-17,18,19-                                             20-tetranor-1-homo-13-trans-pros-                                              tanoic acid                                      106  37         2-(7-carboxyheptyl)-4-hy-                                                                    nat-15S,16R-(and ent-15R,16S)-11α,-                        droxycyclopent-2-en-1-one                                                                    15-dihydroxy-9-oxo-15,16-tetramethy-                                           lene-1-homo-13-trans-prostenoic acid             107  38         2-(7-carboxyheptyl)-4-hy-                                                                    nat-15S,16S-(and ent-15R,16R)-11α,-                        droxycyclopent-2-en-1-one                                                                    15-dihydroxy-9-oxo-15,16-tetramethy-                                           lene-1-homo-13-trans-prostenoic acid             108  41         2-(7-carboxyheptyl)-4-hy-                                                                    nat-15R,16S-(and ent-15S,16R)-11α,-                        droxycyclopent-2-en-1-one                                                                    15-dihydroxy-9-oxo-15,16-trimethy-                                             lene-16-(4-fluorophenoxy)-1-homo-                                              17,18,19,20-tetranor-13-trans-                                                 prostenoic acid                                  109  42         2-(7-carboxyheptyl)-4-hy-                                                                    nat-15R,16R-(and ent-15S,16S)-11α,-                        droxycyclopent-2-en-1-one                                                                    15-dihydroxy-9-oxo-15,16-trimethy-                                             lene-16-(4-fluorophenoxy)-1-homo-                                              17,18,19,20-tetranor-13-trans-                                                 prostenoic acid                                  110  45         2-(8-carboxyoctyl)-4-hy-                                                                     nat-15S,17R-(and ent-15R,17S)-11α,-                        droxycyclopent-2-en-1-one                                                                    15-dihydroxy-9-oxo-15,17-trimethy-                                             lene-19,20-dinor-1a,1b-dihomo-13-                                              -   trans-prostenoic acid                        111  46         2-(8-carboxyoctyl)-4-hy-                                                                     nat-15S,17S-(and ent-15R,17R)-11α,-                        droxycyclopent-2-en-1-one                                                                    15-dihydroxy-9-oxo-15,17-trimethyl-                                            lene-19,20-dinor-1a,1b-dihomo-13-                                              trans-prostenoic acid                            112  47         2-(8-carboxyoctyl)-4-hy-                                                                     nat-16R,17S-(and ent-16S,17R)-11α,-                        droxycyclopent-2-en-1-one                                                                    16-dihydroxy-9-oxo-16,17-trimethy-                                             lene-20-methyl-1a,1b-dihomo-13-                                                trans-prostenoic acid                            113  48         2-(8-carboxyoctyl)-4-hy-                                                                     nat-16R,17R-(and ent-16S,17S)-11α,-                        droxycyclopent-2-en-1-one                                                                    16-dihydroxy-9-oxo-16,17-trimethy-                                             lene-20-methyl-1a,1b-dihomo-13-                                                trans-prostenoic acid                            114  49         2-(8-carboxyoctyl)-4-hy-                                                                     nat-16R,17S-(and ent-16S,17R)-11α,-                        droxycyclopent-2-en-1-one                                                                    16-dihydroxy-9-oxo-16,17-trimethy-                                             lene-16-(3-trifluoromethylphenoxy)-                                            18,19,20-trinor-1a,1b-dihomo-13-                                               trans-prostenoic acid                            115  50         2-(8-carboxyoctyl)-4-hy-                                                                     nat-16R,17R-(and ent-16S,17S)-11α,-                        droxycyclopent-2-en-1-one                                                                    16-dihydroxy-9-oxo-16,17-trimethy-                                             lene-16-(3-trifluoromethylphenoxy)-                                            18,19,20-trinor-1a,1b-dihomo-13-                                               trans-prostenoic acid                            116   29a       2-(6-carboxyhex-2-cis-                                                                       nat-15S,16R-(and ent-15R,16S)-11α,-                        enyl)-4-hydroxycyclo-                                                                        15-dihydroxy-9-oxo-15,16-trimethy-                               pent-2-en-1-one                                                                              lene-13-trans-5-cis-prostadienoic                                              acid                                             117  36         2-(6-carboxyhex-2-cis-                                                                       nat-15S,16S-(and ent-15R,16R)-11α,-                        enyl)-4-hydroxycyclo-                                                                        15-dihydroxy-9-oxo-15,16-trimethy-                               pent-2-en-1-one                                                                              lene-13-trans-5-cis-prostadienoic                                              acid                                             118  32         2-(6-carboxyhex-2-cis-                                                                       nat-(and ent)-11α,-15-dihydroxy-9-                         enyl)-4-hydroxycyclo-                                                                        oxo-15,16-trimethylene-17,18,19,-                                pent-2-en-1-one                                                                              20-tetranor-13-trans-5-cis-prosta-                                             dienoic acid                                     119  33         2-(6-carboxyhex-2-cis-                                                                       nat-(and ent)-11α,15-dihydroxy-9-                          enyl)-4-hydroxycyclo-                                                                        oxo-15,16-pentamethylene-17,18,-                                 pent-2-en-1-one                                                                              19,20-tetranor-13-trans-5-cis-                                                 prostadienoic acid                               120  34         2-(6-carboxyhex-2-cis-                                                                       nat-15S,17R-(and ent-15R,17S)-11α,-                        enyl)-4-hydroxycyclo-                                                                        15-dihydroxy-9-oxo-15,17-dimethy-                                pent-2-en-1-one                                                                              lene-13-trans-5-cis-prostadienoic                                              acid                                             121  35         2-(6-carboxyhex-2-cis-                                                                       nat-15S,17S-(and ent-15R,17R)-11α,-                        enyl)-4-hydroxycyclo-                                                                        15-dihydroxy-9-oxo-15,17-dimethy-                                pent-2-en-1-one                                                                              lene-13-trans-5-cis-prostadienoic                                              acid                                             122  37         2-(6-carboxyhex-2-cis-                                                                       nat-15S,16R-(and ent-15R,16S)-11α,-                        enyl)-4-hydroxycyclo-                                                                        15-dihydroxy-9-oxo-15,16-tetramethyl-                            pent-2-en-1-one                                                                              lene-13-trans-5-cis-prostadienoic                                              acid                                             123  38         2-(6-carboxyhex-2-cis-                                                                       nat-15S,16S-(and ent-15R,16R)-11α,-                        enyl)-4-hydroxycyclo-                                                                        15-dihydroxy-9-oxo-15,16-tetramethy-                             pent-2-en-1-one                                                                              lene-13-trans-5-cis-prostadienoic                                              acid                                             124  39         2-(6-carboxyhex-2-cis-                                                                       nat-15R,16S-(and ent-15S,16R)-11α,-                        enyl)-4-hydroxycyclo-                                                                        15-dihydroxy-9-oxo-15,16-trimethy-                               pent-2-en-1-one                                                                              lene-16-(3-trifluoromethylphenoxy)-                                            17,18,19,20-tetranor-13-trans-5-                                               cis-prostadienoic acid                           125  40         2-(6-carboxyhex-2-cis-                                                                       nat-15R,16R-(and ent-15S,16S)-11α,-                        enyl)-4-hydroxycyclo-                                                                        15-dihydroxy-9-oxo-15,16-trimethy-                               pent-2-en-1-one                                                                              lene-16-(3-trifluoromethylphenoxy)-                                            17,18,19,20-tetranor-13-trans-5-                                               cis-prostadienoic acid                           126  41         2-(6-carboxyhex-2-cis-                                                                       nat-15R,16S-(and ent-15S,16R)-11α,-                        enyl)-4-hydroxycyclo-                                                                        15-dihydroxy-9-oxo-15,16-trimethy-                               pent-2-en-1-one                                                                              lene-16-(4-fluorophenoxy)-17,18,19-                                            20-tetranor-13-trans-5-cis-prosta-                                             dienoic acid                                     127  42         2-(6-carboxyhex-2-cis-                                                                       nat-15R,16R-(and ent-15S,16S)-11α,-                        enyl)-4-hydroxycyclo-                                                                        15-dihydroxy-9-oxo-15,16-trimethy-                               pent-2-en-1-one                                                                              lene-16-(4-fluorophenoxy)-17,18,19,-                                           20-tetranor-13-trans-5-cis-prosta-                                             dienoic acid                                     128  43         2-(6-carboxyhex-2-cis-                                                                       nat-15R,16S-(and ent-15S,16R)-11α,-                        enyl)-4-hydroxycyclo-                                                                        15-dihydroxy-9-oxo-15,16-trimethy-                               pent-2-en-1-one                                                                              lene-16-(3-chlorophenoxy)-17,18,-                                              19,20-tetranor-13-trans-5-cis-pros-                                            tadienoic acid                                   129  44         2-(6-carboxyhex-2-cis-                                                                       nat-15R,16R-(and ent-15S,16S)-11α,-                        enyl)-4-hydroxycyclo-                                                                        15-dihydroxy-9-oxo-15,16-trimethy-                               pent-2-en-1-one                                                                              lene-16-(3-chlorophenoxy)-17,18,-                                              19,20-tetranor-13-trans-5-cis-pros-                                            tadienoic acid                                   130  45         2-(6-carboxyhex-2-cis-                                                                       nat-15S,17R-(and ent-15R,17S)-11α,-                        enyl)-4-hydroxycyclo-                                                                        15-dihydroxy-9-oxo-15,17-trimethy-                               pent-2-en-1-one                                                                              lene-19,20-dinor-13-trans-5-cis-                                               prostadienoic acid                               131  46         2-(6-carboxyhex-2-cis-                                                                       nat-15S,17S-(and ent-15R,17R)-11α,-                        enyl)-4-hydroxycyclo-                                                                        15-dihydroxy-9-oxo-15,17-trimethy-                               pent-2-en-1-one                                                                              lene-19,20-dinor-13-trans-5-cis-                                               prostadienoic acid                               132  47         2-(6-carboxyhex-2-cis-                                                                       nat-16R,17S-(and ent-16S,17R)-11α,-                        enyl)-4-hydroxycyclo-                                                                        16-dihydroxy-9-oxo-16,17-trimethy-                               pent-2-en-1-one                                                                              lene-20-methyl-13-trans-5-cis-pros-                                            tadienoic acid                                   133  48         2-(6-carboxyhex-2-cis-                                                                       nat-16R,17R-(and ent-16S,17S)-11α,-                        enyl)-4-hydroxycyclo-                                                                        16-dihydroxy-9-oxo-16,17-trimethy-                               pent-2-en-1-one                                                                              lene-20-methyl-13-trns-5-cis-pros-                                             tadienoic acid                                   134  49         2-(6-carboxyhex-2-cis-                                                                       nat-16R,17S-(and ent-16S,17R)-11α,-                        enyl)-4-hydroxycyclo-                                                                        16-dihydroxy-9-oxo-16,17-trimethy-                               pent-2-en-1-one                                                                              lene-17-(3-trifluoromethylphenoxy)-                                            18,19,20-trinor-13-trans-5-cis-                                                prostadienoic acid                               135  50         2-(6-carboxyhex-2-cis-                                                                       nat-16R,17R-(and ent-16S,17S)-11α,-                        enyl)-4-hydroxycyclo-                                                                        16-dihydroxy-9-oxo-16,17-trimethy-                               pent-2-en-1-one                                                                              lene-17-(3-trifluoromethylphenoxy)-                                            18,19,20-trinor-13-trans-5-cis-                                                prostadienoic acid                               136   29a       2-(8-carboxyoct-2-cis-                                                                       nat-15S,16R-(and ent-15R,16S)-11α-                         enyl)-4-hydroxycyclo-                                                                        15-dihydroxy-9-oxo-15,16-trimethy-                               pent-2-en-1-one                                                                              lene-1a,1b-dihomo-13-trans-5-cis-                                              prostadienoic acid                               137  36         2-(8-carboxyoct-2-cis-                                                                       nat-15S,16S-(and ent-15R,16R)-11α,-                        enyl)-4-hydroxycyclo-                                                                        15-dihydroxy-9-oxo-15,16-trimethy-                               pent-2-en-1-one                                                                              lene-1a,1b-dihomo-13-trans-5-cis-                                              prostadienoic acid                               138  31         2-(8-carboxyoct-2-cis-                                                                       nat-(and ent)-11α,-15-dihydroxy-9-                         enyl)-4-hydroxycyclo-                                                                        oxo-15,16-tetramethylene-1a,1b-di-                               pent-2-en-1-one                                                                              homo-17,18,19,20-tetranor-13-trans-                                            5-cis-prostadienoic acid                         139  37         2-(8-carboxyoct-2-cis-                                                                       nat-15S,16R-(and ent-15R,16S)-11α,-                        enyl)-4-ydroxycyclo-                                                                         15-dihydroxy-9-oxo-15,16-tetramethy-                             pent-2-en-1-one                                                                              lene-1a,1b-dihomo-13-trans-5-cis-                                              prostadienoic acid                               140  38         2-(8-carboxyoct-2-cis-                                                                       nat-15S,16S-(and ent-15R,16R)-11α,-                        enyl)-4-hydroxycyclo-                                                                        15-hydroxy-9-oxo-15,16-tetramethy-                               pent-2-en-1-one                                                                              lene-1a,1b-dihomo-13-trans-5-cis-                                              prostadienoic acid                               141  39         2-(8-carboxyoct-2-cis-                                                                       nat-15R,16S-(and ent-15S,16R)-11α,-                        enyl)-4-hydroxycyclo-                                                                        15-dihydroxy-9-oxo-15,16-trimethy-                               pent-2-en-1-one                                                                              lene-16-(3-trifluoromethylphenoxy)-                                            1a,1b-dihomo-17,18,19,20-tetranor-                                             13-trans-5-cis-prostadienoic acid                142  40         2-(8-crboxyoct-2-cis-                                                                        nat-15R,16R-(and ent-15S,16S)-11α,-                        enyl)-4-hydroxycyclo-                                                                        15-dihydroxy-9-oxo-15,16-trimethy-                               pent-2-en-1-one                                                                              lene-16-(3-trifluoromethylphenoxy)-                                            1a,1b-dihomo-17,18,19,20-tetranor-                                             13-trans-5-cis-prostadienoic acid                143   29a       2-(6-carboxy-5-oxa-hex-                                                                      nat-15S,16R-(and ent-15R,16S)-11α,-                        yl)-4-hydroxycyclopent-                                                                      15-dihydroxy-3-oxa-9-oxo-15,16-tri-                              2-en-1-one    methylene-13-trans-prostenoic acid               144  36         2-(6-carboxy-5-oxa-hex-                                                                      nat-15S,16S-(and ent-15R,16R)-11α,-                        yl)-4-hydroxycyclopent-                                                                      15-dihydroxy-3-oxa-9-oxo-15,16-tri-                              2-en-1-one    methylene-13-trans-prostenoic acid               145  31         2-(6-carboxy-5-oxa-hex-                                                                      nat-(and ent)-11α,-15-dihydroxy-3-                         yl)-4-hydroxycyclopent-                                                                      oxa-9-oxo-15,16-tetramethylene-                                  2-en-1-one    17,18,19,20-tetranor-13-trans-                                                 prostenoic acid                                  146  43         2-(6-carboxy-4-methyl-                                                                       nat-15R,16S-(and ent-15S,16R)-11α,-                        hex-2-cis-enyl)-4-hydroxy-                                                                   15-dihydroxy-4-methyl-9-oxo-15,16-                               cyclopent-2-en-1-one                                                                         trimethylene-16-(3-chloropenoxy)-                                              17,18,19,20-tetranor-                                                          5-cis-13-trans-                                                                prostadienoic acid                               147  44         2-(6-carboxy-4-methyl-                                                                       nat-15R,16R-(and ent-15S,16S)-11α,-                        hex-2-cis-enyl)-4-hydroxy-                                                                   15-dihydroxy-4-methyl-9-oxo-15,16-                               cyclopent-2-en-1-one                                                                         trimethylene-16-(3-chlorophenoxy)-                                             17,18,19,20-tetranor-                                                          5-cis-13-trans-                                                                prostadienoic acid                               148  45         2-(6-carboxy-4-methyl-                                                                       nat-15S,17R-(and ent-15R,17S)-11α,-                        hex-2-cis-enyl)-4-hydroxy-                                                                   15-dihydroxy-4-methyl-9-oxo-15,17-                               cyclopent-2-en-1-one                                                                         trimethylene-19,20-dinor-                                                      5-cis-13-trans-                                                                prostadienoic acid                               149  46         2-(6-carboxy-4-methyl-                                                                       nat-15S,17S-(and ent-15R,17R)-11α,-                        hex-2-cis-enyl)-4-hydroxy-                                                                   15-dihydroxy-4-methyl-9-oxo-15,17-                               cyclopent-2-en-1-one                                                                         trimethylene-19,20-dinor-13-trans-                                             prostenoic acid                                  150  47         2-(6-carboxy-4-methyl-                                                                       nat-16R,17S-(and ent-16S,17R)-11α,-                        hex-2-cis-enyl)-4-hydroxy-                                                                   16-dihydroxy-4-methyl-9-oxo-16,17-                               cyclopent-2-en-1-one                                                                         trimethylene-20-methyl-13-trans-                                               prostenoic acid                                  151  48         2-(6-carboxy-4-ethylhex-                                                                     nat-16R,17R-(and ent-16S,17S)-11α,-                        2-cis-enyl)-4-hydroxy-                                                                       16-dihydroxy-4-ethyl-9-oxo-16,17                                 cyclopent-2-en-1-one                                                                         trimethylene-20-methyl-13-trans-                                               prostenoic acid                                  152  49         2-(6-carboxy-4-ethyhex-                                                                      nat-16R,17S-(and ent-16S,17R)-11α,-                        2-cis-enyl)-4-hydroxy-                                                                       16-dihydroxy-4-ethyl-9-oxo-15,17-                                cyclopent-2-en-1-one                                                                         trimethylene-17-(3-trifluoromethyl-                                            phenoxy)-18,19,20-trinor-13-trans-                                             prostenoic acid                                  153  50         2-(6-carboxy-4-ethyhex-                                                                      nat-16R,17R-(and ent-16S,17S)-11α,-                        2-cis-enyl)-4-hydroxy-                                                                       16-dihydroxy-4-ethyl-9-oxo-15,17-                                cyclopent-2-en-1-one                                                                         trimethylene-1-(3-trifluoromethyl-                                             phenoxy)-18,19,20-trinor-13-trans-                                             prostenoic acid                                  __________________________________________________________________________

EXAMPLES 154-171

In the manner of Examples 67-70 the 9-oxo-11α-hydroxy prostaglandin methyl esters listed in Table V are prepared from the indicated cyclopent-2-en-1-one and vinyl iodide or vinyl tin compound indicated.

In those cases where two diastereoisomers are formed in the conjugate-addition both are obtained in an optically active form and only one of the diastereoisomers is listed in Table V. It should be understood that the other diastereoisomer is also formed which in its nat or ent forms has an opposite (mirror image) configuration at the assymmetric carbon atoms on the β-chain (the chain containing C₁₃ -C₁₄ . . . etc.) to that of the respective nat or ent forms of the listed diastereoisomer; both of these diastereoisomers are claimed in this invention.

                                      Table V                                      __________________________________________________________________________                                              Product optically active 9-oxo-             Vinyl Iodide or Vinyl              prostaglandin and its optically       Example                                                                              Tin of Example                                                                               Cyclopent-2-en-1-one active diastereoisomer                __________________________________________________________________________     154   29a           2-(6-carbomethoxyhexyl)-4(R)-                                                                       nat-methyl-15S,16R-11α,15-d                                              ihydroxy- -  trimethylosilyoxycyc                                              lo- 9-oxo-15,16-trimethylene-13-t                                              rans-                                                     pent-2-en-1-one      prostenoate                           155   36            2-(6-carbomethoxyhexyl)-4(R)-                                                                       nat-methyl-15S,16S-11α,15-d                                              ihydroxy-                                                 trimethylosilyoxycyclo-                                                                             9-oxo-15,16-trimethylene-13-trans                                              -                                                         pent-2-en-1-one      prostenoate                           156   31            2-(6-carbomethoxyhexyl)-4(R)-                                                                       nat-methyl-11α,15-dihydroxy                                              -9-oxo-                                                   trimethylosilyoxycyclo-                                                                             15,16-tetramethylene-17,18,19,20-                                              N                                                         pent-2-en-1-one      tetranor-13-trans-prostenoate         157   30            2-(6-carbomethoxyhexyl)-4(R)-                                                                       nat-methyl-11α,16-dihydroxy                                              -9-oxo-                                                   trimethylosilyoxycyclo-                                                                             16,17-tetramethylene-18,19,20-tri                                              -                                                         pent-2-en-1-one      nor-13-trans-prostenoate              158   39            2-(6-carbomethoxyhexyl)-4(R)-                                                                       nat-methyl-15R,16S-11α,15-d                                              ihydroxy-                                                 trimethylosilyoxycyclo-                                                                             9-oxo-15,16-trimethylene-16-(3-tr                                              i-                                                        pent-2-en-1-one      fluoromethylphenoxy)-17,18,19,20-                                              tetranor-13-trans-prostenoate         159   40            2-(6-carbomethoxyhexyl)-4(R)-                                                                       nat-methyl-15R,16R-11α,15-d                                              ihydroxy-                                                 trimethylosilyoxycyclo-                                                                             9-oxo-15,16-trimethylene-16-(3-tr                                              i-                                                        pent-2-en-1-one      fluoromethylphenoxy)-17,18,19,20-                                              tetranor-13-trans-prostenoate         160   29a           2-(6-carbomethoxyhexyl)-4(S)-                                                                       ent-methyl-15R,16S-11α,15-d                                              ihydroxy-                                                 trimethylsilyoxycyclo-                                                                              9-oxo-15,16-trimethylene-13-trans                                              -                                                         pent-2-en-1-one      prostenoate                           161   36            2-(6-carbomethoxyhexyl)-4(S)-                                                                       ent-methyl-15R,16R-11α,15-d                                              ihydroxy-                                                 trimethylsilyoxycyclo-                                                                              9-oxo-15,16-trimethylene-13-trans                                              -                                                         pent-2-en-1-one      prostenoate                           162   31            2-(6-carbomethoxyhexyl)-4(S)-                                                                       ent-methyl-11α,15-dihydroxy                                              -9-oxo-                                                   trimethylsilyoxycyclo-                                                                              15,16-tetramethylene-17,18,19,20-                         pent-1-en-1-one      tetranor-13-trans-prostenoate         163   30            2-(6-carbomethoxyhexyl)-4(S)-                                                                       ent-methyl-11α,16-dihydroxy                                              -9-oxo-                                                   trimethylsilyoxycyclo-                                                                              16,17-tetramethylene-18,19,20-tri                                              -                                                         pent-2-en-1-one      nor-13-trans-prostenoate              164   39            2-(6-carbomethoxyhexyl)-4(S)-                                                                       ent-methyl-15S,16R-11α,15-d                                              ihydroxy-                                                 trimethylsilyoxycyclo-                                                                              9-oxo-15,16-trimethylene-16-(3-tr                                              i-                                                        pent-2-en-1-one      fluoromethylphenoxy)-17,18,19,20-                                              tetranor-13-trans-prostenoate         165   40            2-(6-carbomethoxyhexyl)-4(S)-                                                                       ent-methyl-15S,16S-11α,15-d                                              ihydroxy-                                                 trimethylsilyoxycyclo-                                                                              9-oxo-15,16-trimethylene-16-(3-tr                                              i-                                                        pent-2-en-1-one      fluoromethylphenoxy)-17,18,19,20-                                              tetranor-13-trans-prostenoate         166   29a           2-(6-carbomethoxyhex-2-                                                                             nat-methyl-15S,16R-11α,15-d                                              ihydroxy-                                                 cis-enyl)-4(R)-trimeth-                                                                             9-oxo-15,16-trimethylene-13-trans                                              -                                                         ylsilyoxycyclopent-  5-cis-prostenoate                                         2-en-1-one                                                 167   36            2-(6-carbomethoxyhex-2-                                                                             nat-methyl-15S,16S-11α,15-d                                              ihydroxy-                                                 cis-enyl)-4(R)-trimeth-                                                                             9-oxo-15,16-trimethylene-13-trans                                              -                                                         ylsilyoxycyclopent-  5-cis-prostadienoate                                      2-en-1-one                                                 168   31            2-(6-carbomethoxyhex-2-                                                                             nat-methyl-11α,15-dihydroxy                                              -9-oxo-                                                   cis-enyl)-4(R)-trimeth-                                                                             15,16-tetramethylene-17,18,19,20-                         ylsilyoxycyclopent-  tetraor-13-trans-5-cis-prosta-                            2-en-1-one           dienoate                              169   30            2-(6-carbomethoxyhex-2-                                                                             nat-methyl-11α,16-dihydroxy                                              -9-oxo-                                                   cis-enyl)-4(R)-trimeth-                                                                             16,17-tetramethylene-18,19,20-tri                                              -                                                         ylsilyoxycyclopent-2-                                                                               nor-13-trans-5-cis-prostadienoate                                              O                                                         en-1-one                                                   170   39            2-(6-carbomethoxyhex-2-                                                                             nat-methyl-15R,16S-11α,15-d                                              ihydroxy-                                                 cis-enyl)-4(R)-trimeth-                                                                             9-oxo-15,16-trimethylene-16-(3-tr                                              i-                                                        ylsilyoxycyclopent-2-                                                                               fluoromethylphenoxy)-17,18,19,20-                         en-1-one             tetranor-13-trans-5-cis-prosta-                                                dienoate                              171   40            2-(6-carbomethoxyhex-2-                                                                             nat-methyl-15R,16R-11α,15-d                                              ihydroxy-                                                 cis-enyl)-4(R)-trimeth-                                                                             9-oxo-15,16-trimethylene-16-(3-tr                                              i-                                                        ylsiloxycyclopent-2- fluoromethylphenoxy)-17,18,19,20-                         en-1-one-            tetranor-13-trans-5-cis-prosta-                                                dienoate                              172   31            2-(6-carbotrimethylsilyl-                                                                           nat-(and ent)-11α,15-dihydr                                              oxy-3-                                                    oxy-5-thiahexyl)-4-tri-                                                                             thia-9-oxo-15,16-trimethylene-                            methylsilyloxycyclo- 17,18,19,20-tetranor-13-trans-                            pent-2-en-1-one      prostenoic acid                       173   29a           2-(6-carbotrimethylsilyl-                                                                           nat-15S,16R(and                                                                ent-15R,16S)-11α,15-                                oxy-5-thiahexyl)-4-tri-                                                                             dihydroxy-3-thia-9-oxo-15,16-tri-                         methylsilyloxycyclo- methylene-13-trans-prostenoic                                                  acid                                                      pent-2-en-1-one                                            174   36            2-(6-carbotrimethylsilyl-                                                                           nat-15S, ent-15R,16R)-11α,-                         oxy-5-thiahexyl)-4-tri-                                                                             15-dihydroxy-3-thia-9-oxo-15,16-t                                              ri-                                                       methylsilyloxycyclo- methylene-13-trans-prostenoic                                                  acid                                                      pent-2-en-1-one                                            175   30            2-(6-carbotrimethylsilyl-                                                                           nat-(and ent)-11α,16-dihydr                                              oxy-3-                                                    oxy-5-thiahexyl)-4-tri-                                                                             thia-9-oxo-16,17-tetramethylene-                                               S                                                         methylsilyloxycyclo- 18,19,20-trinor-13-trans-prosteno                                              ic                                                        pent-2-en-1-one      acid                                  176   39            2-(6-carbotrimethylsilyl-                                                                           nat-15R,16S-(and                                                               ent-15S,16R)-11α,-                                  oxy-5-thiahexyl)-4-tri-                                                                             15-dihydroxy-3-thia-9-oxo-15,16-t                                              ri-                                                       methylsilyloxycyclo- methylene-16-(3-trifluoromethyl-                                               O                                                         pent-2-en-1-one      phenoxy)-17,18,19,20-tetranor-13-                                              trans-prostenoic acid                 177   40            2-(6-carbotrimethylsilyl-                                                                           nat-15R,16R-(and                                                               ent-15S,16S)-11α,-                                  oxy-5-thiahexyl)-4-tri-                                                                             15-dihydroxy-3-thia-9-oxo-15,16-t                                              ri-                                                       methylsilyloxycyclo- methylene-16-(3-trifluoromethyl-                          pent-2-en-1-one      phenoxy)-17,18,19,20-tetranor-13-                                              trans-prosteoic acid                  178   31            2-(5-carbotrimethylsilyl-                                                                           nat-(and ent)-11α,-15-dihyd                                              roxy-3-                                                   oxy-4-thiapentyl)-4-tri-                                                                            thia-9-oxo-15,16-tetramethylene-                          methylsilyloxycyclopent-                                                                            4,17,18,19,20-pentanor-13-trans-                          2-en-1-one           prostenoic acid                       179   29a           2-(5-carbotrimethylsilyl-                                                                           nat-15S,16R-(and                                                               ent-15R,16S-11α,-                                   oxy-4-thiapentyl)-4-tri-                                                                            15-dihydroxy-3-thia-9-oxo-15,16-t                                              ri-                                                       methylsilyloxycyclopent-                                                                            methylene-4-nor-13-trans-prosteno                                              ic                                                        2-en-1-one           acid                                  180   36            2-(5-carbotrimethylsilyl-                                                                           nat-15S,16S-(and                                                               ent-15R,16R)-11α,-                                  oxy-4-thiapentyl)-4-tri-                                                                            15-dihydroxy-3-thia-9-oxo-15,16-t                                              ri-                                                       methylsilyloxycyclopent-                                                                            methylene-4-nor-13-trans-prosteno                                              ic                                                        2-en-1-one           acid                                  181   30            2-(5-carbotrimethylsilyl-                                                                           nat-(and ent)-11α,16-dihydr                                              oxy-3-                                                    oxy-4-thiapentyl)-4-tri-                                                                            thia-9-oxo-16,17-tetramethylene-4                                              -,-                                                       methylsilyloxycyclopent-                                                                            18,19,20,tetranor-13-trans-proste                                              ne-                                                       2-en-1-one           oic acid                              182   39            2-(5-carbotrimethylsilyl-                                                                           nat-15R,16S-(and                                                               ent-15S,16R)-11α,-                                  oxy-4-thiapentyl)-4-tri-                                                                            15-dihydroxy-3-thia-9-oxo-15,16-                                               9                                                         methylsilyloxycyclopent-                                                                            trimethylene-16-(3-trifluoromethy                                              l-                                                        2-en-1-one           phenoxy)-4,17,18,19,20-pentaor-13                                              -                                                                              trans-prostenoic acid                 183   40            2-(5-carbotrimethylsilyl-                                                                           nat-15R,16R-(and                                                               ent-15S,16S)-11α,-                                  oxy-4-thiapentyl)-4-tri-                                                                            15-dihydroxy-3-thia-9-oxo-15,16-t                                              ri-                                                       methylsilyloxycyclopent-                                                                            methylene-16 (3-trifluoromethyl-                          2-en-1-one           phenoxy)-4,17,18,19,20-pentanor-1                                              3- -   trans-prostenoic               __________________________________________________________________________                                              acid                             

EXAMPLE 184 Preparation of methyl nat(and ent)-11α,15-dihydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-5-cis-13-trans-prostadienoate

To an ethereal solution of 0.10 g of nat(and ent)-11α,15-dihydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid is added an excess of ethereal diazomethane. After 5 minutes the excess diazomethane and the solvent is blown off with a stream of nitrogen to give the titled methyl ester.

EXAMPLES 185-190

In the manner of Example 426 described above, the prostaglandins listed in Table VI are esterified with the indicated diazoalkanes.

                                      Table VI                                     __________________________________________________________________________          Prostaglandin of                                                          Example                                                                             Example  Diazoalkane                                                                            Product esterified prostaglandin                         __________________________________________________________________________     185  69       diazomethane                                                                           methyl nat-(and ent)-11α,16-dihydroxy-9-                                 oxo-16,17-tetramethylene-18,19,20-trinor-                                      5-cis-13-trans-prostadienoate                            186  72       diazoethane                                                                            ethyl nat-15S,16R-(and ent-15R,16S)-11α,-15-                             dihydroxy-9-oxo-15,16-trimethylene-13-                                         trans-prostenoate                                        187  73       1-diazopropane                                                                         n-propyl nat-15S,16S-(and ent-15R,16S)-                                        11α,15-dihydroxy-9-oxo-15,16-trimethylene-                               13-trans-prostenoate                                     188  74       diazomethane                                                                           methyl-nat-(and ent)-11α,15-dihydroxy-9-                                 oxo-15,16-tetramethylene-17,18,19,20-                                          tetranor-13-trans-prostenoate                            189  86       1-diazohexane                                                                          n-hexyl-nat-15S,16R-(and ent-15R,16S)-11α,-                              15-dihydroxy-9-oxo-15,16-trimethylene-5-                                       cis-13-trans-prostadienoate                              190  191      diazomethane                                                                           methyl-nat-(and ent)-11α,-15-dihydroxy-9-oxo-                            15,16-tetramethylene-17,18,19,20-tetra-                                        nor-5-cis-13-trans-prostadienoate                        __________________________________________________________________________

EXAMPLE 191 Preparation of nat(and ent)-9α,11α,15-Trihydroxy-15,16-tetramethylene-17,18,19,20-tetranor-13-trans-5-cis-prostadienoic Acid

To a solution of 1.25 g of nat(and ent)-11α,15-dihydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-13-trans-5-cis-prostadienoic acid in 20 ml of tetrahydrofuran at -78° C. under nitrogen is added with stirring 21.4 ml of 0.5 M lithium perhydro-9b-borophenalylhydride in tetrahydrofuran. After stirring 30 minutes at -78° C. the solution is allowed to warm to 0° C. over a one hour period and then poured into dilute sodium carbonate solution. The aqueous mixture is extracted three times with ether. The aqueous layer is separated and one ml of 30% hydrogen peroxide is added. After 10 minutes the aqueous solution is acidified with HCl and extracted with ethyl acetate. The ethyl acetate solution is dried over magnesium sulfate and the solvent is removed to give 1.14 g of the desired product as a yellow oil.

EXAMPLE 192 Preparation of nat-15S,16R(and ent-15R,16S) and nat-15R,16S(and ent-15S,16R)-9α,11α,15 -Trihydroxy-15,16-trimethylene-13-trans-prostadienoic Acid

To a solution of 1.12 g of a mixture of the 9-oxo analogs of the above named compounds in 20 ml of tetrahydrofuran under nitrogen at -78° C. is added with stirring 20 ml of 0.5 M lithium perhydro-9b-boraphenalylhydride in tetrahydrofuran. After stirring 30 minutes at -78° C., the solution is allowed to warm to 0° C. over a one hour period. The mixture is poured into dilute sodium carbonate solution and this mixture is washed with ether several times. To the aqueous solution is added 3 ml of 30% hydrogen peroxide. After 10 minutes the solution is acidified with hydrochloric acid and extracted with ethyl acetate. The extract is dried with magnesium sulfate and activated charcoal and the solvent is removed giving a light yellow oil. This oil is chromatographed on a silica gel dry column, eluting with ethyl acetate giving the desired mixed isomers as oils.

EXAMPLE 193 Preparation of nat(and ent)-9α,11α,16-Trihydroxy-9-oxo-16,17-tetramethylene-18,19,20-trinor-5-cis-13-trans-prostadienoic Acid

A 1.9 g portion of nat(and ent)-11α,16-dihydroxy-9-oxo-16,17-tetramethylene-18,19,20-trinor-5-cis-13-transprostadienoic acid is purified by chromatography eluting with increasing gradients of initial 30% ethylacetate in hexane totaling 3.5 liters. A 510 mg portion of purified material is obtained.

A 400 mg portion of this purified material is dissolved in 5 ml of freshly distilled tetrahydrofuran and cooled in a dry-ice-acetone bath under nitrogen. A 5 ml portion of lithium selectride (1 M in 1:1 pentane:tetrahydrofuran) is added over a 10 minute period. After stirring for one hour, 5 ml of water is added and the cooling bath is removed. The mixture is stirred for another hour. The mixture is acidified with 4 N HCl and extracted with ether. The ether extracts are combined, washed with water and brine and the solvent is evaporated to dryness. The residue is dissolved in 3 ml of tetrahydrofuran and cooled in an ice bath. It is then treated successively with one ml of 2.5 N sodium hydroxide and 0.8 ml of 30% hydrogen peroxide and stirred in the ice bath under nitrogen for 25 minutes. The mixture is diluted with water, acidified with 4 N hydrochloric acid and extracted with a combination of ether and ethyl acetate. The combined organic extract is washed with water and brine. The solvent is evaporated to dryness on a rotary evaporator. The residue is spotted on a 2×2000u thin layer chromatography silica gel plate and developed with 1% acetic acid in ethyl acetate. The product is detected by iodine vapor and washed off the silica gel using 100 ml of ethyl acetate and 300 ml of 20% methanol in chloroform. The solvents are evaporated in the presence of toluene using a rotary evaporator followed by vacuum. The desired product is crystallized from chloroform.

EXAMPLES 194-223

In the manner described hereinabove for Examples 191-193 the 9-oxo-prostaglandins indicated in Table VII reduced with lithium perhydro-9b-borophenalylhydride or lithium selectride to give the indicated 9α-hydroxy compounds.

                                      Table VII                                    __________________________________________________________________________          9-oxo-prostaglandin of                                                    Example                                                                             Example    Product 9α-hydroxy prostaglandin                         __________________________________________________________________________     194   72        nat-15S,16R-(and ent-15R,16S)-9α,11α,15-trihyd                     roxy-                                                                          15,16-trimethylene-13-trans-prostenoic acid                    195   73        nat-15S,16S-(and ent-15R,16R)-9α,11α,15-trihyd                     roxy-                                                                          15,16-trimethylene-13-trans-prostenoic acid                    196   74        nat-(and ent)-9α,11α,15-trihydroxy-15,16-tetra                     -                                                                              methylene-17,18,19,20-tetranor-13-trans-prostenoic                             acid                                                           197   69        nat-(and ent)-9α,11α,16-trihydroxy-16,17-tetra                     methy-                                                                         lene-18,19,20-trinor-13-trans-5-cis-prostadienoic                              acid                                                           198   81        nat-15R,16S-(and ent-15S,16R)-9α,11α,15-trihyd                     roxy-                                                                          15,16-trimethylene-16-(3-trifluoromethylphenoxy)-                              17,18,19,20-tetranor-13-trans-prostenoic acid                  199   82        nat-15R,16R-(and ent-15S,16S)-9α,11α,15-trihyd                     roxy-                                                                          15,16-trimethylene-16-(3-trifluoromethylphenoxy)-                              17,18,19,20-tetranor-13-trans-prosteoic acid                   200   83        nat-(and ent)-9α,11α,16-trihydroxy-16,17-tetra                     methy-                                                                         lene-18,19,20-trinor-13-trans-prostenoic acid                  201   84        nat-15R,16R-(and ent-15S,16S)-9α,11α,15-trihyd                     roxy-                                                                          15,16-trimethylene-16-(4-fluorophenoxy)-7-homo-                                17,18,19,20-tetranor-13-trans-prostenoic acid                  202  117        nat-15S,16R-(and ent-15R,16S)-9α,11α,15-trihyd                     roxy-                                                                          15,16-trimethylene-13-trans-5-cis-prostadienoic acid           203  117        nat-15S,16S-(and ent-15R,16R)-9α,11α,15-trihyd                     roxy-                                                                          15,16-trimethylene-13-trans-5-cis-prostadienoic acid           204  124        nat-15R,16S-(and ent-15S,16R)-9α,11α,15-trihyd                     roxy-                                                                          15,16-trimethylene-16-(3-trifluoromethylphenoxy)-                              17,18,19,20-tetranor-13-trans-5-cis-prostadienoic                              acid                                                           205  125        nat-15R,16R-(and ent-15S,16S)-9α,11α,15-trihyd                     roxy-                                                                          15,16-trimethylene-16-(3-trifluoromethylphenoxy)-                              17,18,19,20-tetranor-13-trans-5-cis-prostadienoic                              acid                                                           206  126        nat-15R,16S-(and ent-15S,16R)-9α,11α,15-trihyd                     roxy-                                                                          15,16-trimethylene-16-(4-fluorophenoxy)-17,18,19,-                             20-tetranor-13-trans-5-cis-prostadienoic acid                  207  127        nat-15R,16R-(and ent-15S,16S)-9α,11α,15-trihyd                     roxy-                                                                          15,16-trimethylene-16-(4-fluorophenoxy)-17,18,19,-                             20-tetranor-13-trans-5-cis-prostadienoic acid                  208  128        nat-15R,16S-(and ent-15S,16R)-9α,11α,15-trihyd                     roxy-                                                                          15,16-trimethylene-16-(3-chlorophenoxy)-17,18,19,-                             20-tetranor-13-trans-5-cis-prostadienoic acid                  209  129        nat-15R,16R-(and ent-15S,16S)-9α,11α,15-trihyd                     roxy-                                                                          15,16-trimethylene-16-(3-chloropenoxy)-17,18,19,-                              20-tetranor-13-trans-5-cis-prostadienoic acid                  210  134        nat-16R,17S-(and ent-16S,17R)-9α,11α,16-trihyd                     roxy-                                                                          16,17-trimethylene-17-(3-trifluoromethylphenoxy)-                              18,19,20-trinor-13-trans-5-cis-prostadienoic acid              211  135        nat-16R,17R-(and ent-16S,17S)-9α,11α,16-trihyd                     roxy-                                                                          16,17-trimethylene-17-(3-trifluoromethylphenoxy)-                              18,19,20-trinor-13-trans-5-cis-prostadinoic acid               212  136        nat-15R,16R-(and ent-15R,16S)-α,11α,15-trihydr                     oxy-                                                                           15,16-trimethylene-1a,1b-dihomo-13-trans-5-cis-                                prostadienoic acid                                             213  138        nat-(and ent)-9α,11α,15-trihydroxy-15,16-tetra                     methy-                                                                         lene-1a,1b-dihomo-17,18,19,20-tetranor-13-trans-5-                             cis-prostadienoic acid                                         214  144        nat-15S,16S-(and ent-15R,16R)-9α,11α,15-trihyd                     roxy-                                                                          3-oxo-15,16-trimethyl-13-trans-prostenoic acid                 215  145        nat-(and ent)-9α,11α,15-trihydroxy-3-oxa-15,16                     -tetra-                                                                        methylene-17,18,19,20-tetranor-13-trans-prostenoic                             acid                                                           216   78        nat-15S,17S-(and ent-15R,17R)-9α,11α,15-trihyd                     roxy-4-                                                                        methyl-15,17-trimethylene-19,20-dinor-13-trans-                                prostenoic acid                                                217  154        nat-methyl-15S,16R-9α,11α,15-trihydroxy-15,16-                     tri-                                                                           methylene-13-trans-prostenoate                                 218  156        nat-methyl-9α,11α,15-trihydroxy-15,16-tetramet                     hylene-                                                                        17,18,19,20-tetranor-13-trans-prostenoate                      219  157        nat-methyl-9α,11α,16-trihydroxy-16,17-tetramet                     hylene-                                                                        18,19,20-trinor-13-trans-prostenoate                           220  161        ent-methyl-15R,16R-9α,11α,15-trihydroxy-15,16-                     tri- -  methylene-13-trans-prostenoate                         221  166        nat-methyl-15S,16R-9α,11α,15-trihydroxy-15,16-                     tri-                                                                           methylene-13-trans-5-cis-prostadienoate                        222  170        nat-methyl-15R,16S-9α,11α,15-trihydroxy-15,16-                     tri-                                                                           methylene-16-(3-trifluoromethylphenoxy)-17,18,19,-                             20-tetranor-13-trans-5-cis-prostadienoate                      223  171        nat-methyl-15R,16R-9α,11α,15-trihydroxy-15,16-                     tri-                                                                           methylene-16-(3-trifluoromethylphenoxy)-17,18,19,-                             20-tetranor-13-trans-5-cis-prostadienoate                      __________________________________________________________________________

EXAMPLE 224 Preparation of nat(and ent)-9α,15-Dihydroxy-11-oxo-15,16-tetramethylene-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic Acid

To a solution of 0.5 g of nat(and ent)-9α,11α,15-trihydroxy-15,16-tetramethylene-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid in 25 ml of acetone at -35° C., is added dropwise with stirring, 0.67 ml of Jones reagent (2.67 g CrO₃ plus 2.3 ml H₂ SO₄ diluted to 10 ml with water). After 13 minutes 0.4 ml of isopropanol followed by 2 ml of water is added. The mixture is poured into water then saturated with NaCl and extracted with ethyl acetate. The solution is dried over MgSO₄ and the solvent is removed to give a yellow oil. This oil is chromatographed on a dry silica gel column, eluting with ether and 1% acetic acid. The major band is isolated and extracted with ethyl acetate and acetone giving the above product.

EXAMPLE 225 Preparation of nat(and ent)-9α,16-Dihydroxy-11-oxo-16,17-tetramethylene-18,19,20-trinor-5-cis-13-trans-prostadienoic Acid

A 130 mg portion of nat(and ent)-9α,11α,16-trihydroxy-9-oxo-16,17-tetramethylene-18,19,20-trinor-5-cis-13-trans-prostadienoic acid is dissolved in 7 ml of acetone and 2 ml of glacial acetic acid and cooled in a dry ice-acetonitrile bath under nitrogen. A 0.15 ml portion of Jones Reagent is added and the mixture is stirred in the same bath for 2 hours. The temperature of the bath is slowly raised to -20° C. until the color of the mixture turns green. A few drops of isopropanol are added. The mixture is diluted with water and extracted with three 30 ml portions of ether. The combined ether extracts are washed with water and brine. The solvents are evaporated in the presence of toluene to dryness. The residue is passed through a silica gel column packed in 40% ethyl acetate in hexane. Elution with 40-50% ethyl acetate in hexane gives 46 mg of pure product.

EXAMPLES 226-252

In the manner described above for examples 224 and 225 the 9α,11α-hydroxy prostaglandins listed in Table VIII are oxidized with Jones reagent to produce the indicated 9α-11-oxo-prostaglandins.

                                      Table VIII                                   __________________________________________________________________________          9α,11α-dihydroxy-pros-                                        Example                                                                             taglandin of Example                                                                       Product 9α-hydroxy-11-oxo-prostaglandin                 __________________________________________________________________________     226  197         nat-(and ent)-9α,16-dihydroxy-11-oxo-16,17-tetra-                        methylene-18,19,20-trinor-13-trans-5-cis-prosta-                               dienoic acid                                                  227  198         nat-15R,16S-(and ent-15S,16R)-9α,15-dihydroxy-11-ox                      o-                                                                             15,16-trimethylene-16-(3-trifluoromethylphenoxy)-                              17,18,19,20-tetranor-13-trans-prostenoic acid                 228  199         nat-15R,16R-(and ent-15S,16S)-9α,15-dihydroxy-11-ox                      o-                                                                             15,16-trimethylene-16-(3-trifluoromethylphenoxy)-                              17,18,19,20-tetranor-13-trans-prostenoic acid                 229  200         nat-(and ent)-9α,16-dihydroxy-11-oxo-16,17-tetra-                        methylene-18,19,20-trinor-13-trans-prostenoic acid            230  201         nat-15R,16R-(and ent-15S,16S)-9α,15-dihydroxy-11-                        oxo-15,16-trimethylene-16-(4-fluorophenoxy)-7-homo-                            17,18,19,20-tetranor-13-trans-prostenoic acid                 231  202         nat-15S,16R-(and ent-15R,16S)-9α,15-dihydroxy-11-ox                      o-                                                                             15,16-trimethylene-13-trans-5-cis-prostadienoic acid          232  203         nat-15S,16S-(and ent-15R,16R)-9α,15-dihydroxy-11-ox                      o-                                                                             15,16-trimethylene-13-trans-5-cis-prostadienoic acid          233  204         nat-15R,16S-(and ent-15S,16R)-9α,15-dihydroxy-11-ox                      o-                                                                             15,16-trimethylene-16-(3-trifluoromethylphenoxy)-                              17,18,19,20-tetranor-13-trans-5-cis-prostadienoic                              acid                                                          234  205         nat-15R,16R-(and ent-15S,16S)-9α,15-dihydroxy-11-ox                      o-                                                                             15,16-trimethylene-16-(3-trifluoromethylphenoxy)-                              17,18,19,20-tetranor-13-trans-5-cis-prostadienoic                              acid                                                          235  206         nat-15R,16S-(and ent-15S,16R)-9α,15-dihydroxy-11-ox                      o-                                                                             15,16-trimethylene-16-(4-fluorophenoxy)-17,18,19,20-                           tetranor-13-trans-5-cis-prostadienoic acid                    236  207         nat-15R,16R-(and ent-15S,16S)-9α,15-dihydroxy-11-ox                      o-                                                                             15,16-trimethylene-16 (4-fluorophenoxy)-17,18,19,20-                           tetranor-13-trans-5-cis-prostadienoic acid                    237  208         nat-15R,16S-(and ent-15S,16R)-9α                                         ,15-dihydroxy-11-oxo-                                                          15,16-trimethylene-16-(3-chlorophenoxy)-17,18,1-                               tetranor-13-trans-5-cis-prostadienoic acid                    238  209         nat-15R,16R-(and ent-15S,16S)-9α,15-dehydroxy-11-ox                      o-                                                                             15,16-trimethylene-16-(3-chlorophenoxy)-17,18,19,20-                           tetranor-13-trans-5-cis-prostadienoic acid                    239  210         nat-16R,17S-(and ent-16S,17R)-9α,16-dihydroxy-11-ox                      o-                                                                             16,17-trimethylene-1 -(3-trifluoromethylphenoxy)-                              18,19,20-trinor-13-trans-5-cis-prostadienoic acid             240  211         nat-16R,17R-(and ent-16S,17S)-9α,16-dihydroxy-11-ox                      o-                                                                             16,17-trimethylene-1 -(3-trifluoromethylphenoxy)-                              18,19,20-trinor-13-trans-5-cis-prostadienoic acid             241  212         nat-15R,16R-(and ent-15R,16S)-9α,15-dihydroxy-11-ox                      o-                                                                             15,16-trimethylene-1a,1b-dihomo-13-trans-5-cis-                                prostadienoic acid                                            242  213         nat-(and ent)-9α,15-dihydroxy-11-oxo-15,16-tetra-                        methylene-1a,1b-dihomo-17,18,19,20-tetranor-13-trans-                          5-cis-prostadienoic acid                                      243  214         nat-15S,16S-(and ent-15R,16R)-9α,15-dihydroxy-11-ox                      o-                                                                             3-oxa-15,16-trimethylene-13-trans-prostenoic acid             244  215         nat-(and ent)-9α,15-dihydroxy-11-oxo-3-oxa-15,16-                        tetramethylene-17,18,19,20-tetrano-13-trans-                                   prostenoic acid                                               245  216         nat-15S,17S-(and ent-15R,17R)-9α,15-dihydroxy-11-ox                      o-                                                                             4-methyl-15,17-trimethylene-19,20-dinor-13-trans-                              prostenoic acid                                               246  217         nat-methyl-15S,16R-9α,15-dihydroxy-11-oxo-15,16-tri                      -                                                                              methylene-13-trans-prostenoate                                247  218         nat-methyl-9α,15-dihydroxy-11-oxo-15,16-tetramethy-                      e                                                                              lene-17,18,19,20-tetranor-13-trans-prostenoate                248  219         nat-methyl-9α,15-dihydroxy-11-oxo-16,17-tetramethy-                      b                                                                              lene-18,19,20-trinor-13-trans-prostenoate                     249  220         ent-methyl-15R,16R-9α,15-dihydroxy-11-oxo-15,16-tri                      -                                                                              methylene-13-trans-prostenoate                                250  221         nat-methyl-15S,16R-9α,15-dihydroxy-11-oxo-15,16-tri                      -                                                                              methylene-13-trans-5-cis-prostadienoate                       251  222         nat-methyl-15R,16S-9α,15-dihydroxy-11-oxo-15,16-tri                      -                                                                              methylene-16-(3-trifluoromethylphenoxy)-17,18,19,20-                           tetranor-13-trans-5-cis-prostadienoate                        252  223         nat-methyl-15R,16R-9α,11α,15-dihydroxy-11-oxo                      -15,16-                                                                        trimethylene-16-(3-trifluoromethylphenoxy)-17,18,-                             19,20-tetranor-13-trans-5-cis-prostadienoate                  __________________________________________________________________________ 

We claim:
 1. An optically active compound of the formula: ##STR26## wherein R₁ is selected from the group consisting of hydroxy, tri-(C₁ -C₄)-alkylsilyloxy, and C₁ -C₆ alkoxy; R₅ is selected from the group consisting of hydrogen, tri-(C₁ -C₄)-alkylsilyloxy and C₂ -C₅ alkanoyloxy; Y is a trivalent radical selected from the group consisting of a moiety of the formula ##STR27## wherein R₃ is selected from the group consisting of hydrogen tri-(C₁ -C₄)alkylsilyloxy and C₂ -C₅ alkanoyl; X is a divalent radical selected from the group consisting of a moiety of the formula ##STR28## wherein R₄ is selected from the group consisting of C₁ -C₇ alkyl, hydrogen, pehnoxy and phenoxy substituted with a compound selected from the group consisting of halogen, trifluoromethyl and methoxy; n is zero or an integer from 1 to 4; m is zero or an integer from 1 to 4, with the proviso that the sum of n and m has the value of 2 to 4; the moiety C₁₃ -C₁₄ is ethylene or trans-vinylene; w is zero or 1; and Z is a divalent radical selected from the group consisting of a moiety of the formula: ##STR29## wherein p is an integer from 5 to 7, q is an integer from 1 to 3, and t is an integer from 3 to 5; R₅ is selected from the group consisting of hydrogen and C₁ -C₃ alkyl; the racemic mixture thereof; and the pharmacologically acceptable cationic salts thereof when R₁ is hydrogen.
 2. An optically active compound of the formula: ##STR30## wherein R₁ is selected from the group consisting of hydroxy, and C₁ -C₆ alkoxy; Y is a trivalent radical selected from the group consisting of a moiety of the formula: ##STR31## X is a divalent radical selected from the group consisting of a moiety of the formula: ##STR32## wherein R₄ is selected from the group consisting of C₁ -C₇ alkyl, n is zero or an integer from 1 to 4; m is zero or an integer from 1 to 4, with the proviso that the sum of n and m has the value of 2 to 4; the moiety C₁₃ -C₁₄ is ethylene or trans-vinylene; w is zero or 1; and Z is a divalent radical selected from the group consisting of a moiety of the formula: ##STR33## wherein p is an integer from 5 to 7, q is an integer from 1 to 3, and t is an integer from 3 to 5; the racemic mixture, the mirror image thereof; and the pharmacologically acceptable cationic salts thereof when R₁ is hydrogen.
 3. A compound according to claim 2 wherein C₁₃ -C₁₄ is trans-vinylene.
 4. A compound according to claim 3 wherein Z is --(CH₂)₆ -- and --(CH₂)₄ --O--CH₂ --.
 5. A compound according to claim 4 wherein Z is the divalent radical --(CH₂)₆ --.
 6. A compound according to claim 5 wherein W is zero.
 7. A compound according to claim 5 wherein W is one.
 8. A compound according to claim 4, nat.-15S,16R (and ent. 15R,16S)-9α,15-dihydroxy-11-oxo-15,16-trimethylene-3-oxa-13-trans-prostenoic acid.
 9. A compound according to claim 4, nat.-15S,16S (and ent. 15R,16R)-9α,15-dihydroxy-11-oxo-15,16-trimethylene-3-oxa-13-trans-prostenoic acid.
 10. A compound according to claim 4, methyl nat.-15S,16R (and ent.-15R,16S)-9α,15-dihydroxy-11-oxo-15,16-trimethylene-3-oxa-13-trans-prostenoate.
 11. A compound according to claim 4, methyl nat.-15S,16S (and ent.-15R,16R)-9α,15-dihydroxy-11-oxo-15,16-trimethylene-3-oxa-13-trans-prostenoate.
 12. A compound according to claim 6, nat.-15S,16R (and ent. 15R,16S)-9α,15-dihydroxy-11-oxo-15,16-trimethylene-13-trans-prostenoic acid.
 13. A compound according to claim 6, nat.-15S,16R-9α,15-dihydroxy-11-oxo-15,16-trimethylene-13-trans-prostenoic acid.
 14. A compound according to claim 6, methyl nat.-15S,16R (and ent.-15R,16S)-9α,15-dihydroxy-11-oxo-15,16-trimethylene-13-trans-prostenoate.
 15. A compound according to claim 6, methyl nat.-15S,16R-9α,15-dihydroxy-11-oxo-15,16-trimethylene-13-trans-prostenoate.
 16. A compound according to claim 6, nat.-15S,16S (and ent.-15R,16R)-9α,15-dihydroxy-11-oxo-15,16-trimethylene-13-trans-prostenoic acid.
 17. A compound according to claim 6, nat.-15S,16S-9α,15-dihydroxy-11-oxo-15,16-trimethylene-13-trans-prostenoic acid.
 18. A compound according to claim 6, methyl nat.-15S,16S (and ent.-15R,16R)-9α,15-dihydroxy-11-oxo-15,16-trimethylene-13-trans-prostenoate.
 19. A compound according to claim 6, methyl nat.-15S,16S-9α,15-dihydroxy-11-oxo-15,16-trimethylene-13-trans-prostenoate.
 20. A compound according to claim 6, nat.-15S,17R (and ent.-15R,17S)-9α,15-dihydroxy-11-oxo-15,17-dimethylene-13-trans-prostenoic acid.
 21. A compound according to claim 6, nat.-15S,17R-9α,15-dihydroxy-11-oxo-15,17-dimethylene-13-trans-prostenoic acid.
 22. A compound according to claim 6, methyl nat.-15S,17R (and ent.-15R,17S)-9α,15-dihydroxy-11-oxo-15,17-dimethylene-13-trans-prostenoate.
 23. A compound according to claim 6, methyl nat.-15S,17R-9α,15-dihydroxy-11-oxo-15,17-dimethylene-13-trans-prostenoate.
 24. A compound according to claim 6, nat.-15S,17S (and ent.-15R,17R)-9α,15-dihydroxy-11-oxo-15,17-dimethylene-13-trans-prostenoic acid.
 25. A compound according to claim 6, nat.-15S,17S-9α,15-dihydroxy-11-oxo-15,17-dimethylene-13-trans-prostenoic acid.
 26. A compound according to claim 6, methyl nat.-15S,17S (and ent.-15R,17R)-9α,15-dihydroxy-11-oxo-15,17-dimethylene-13-trans-prostenoate.
 27. A compound according to claim 6, methyl nat.-15S,17S-9α,15-dihydroxy-11-oxo-15,17-dimethylene-13-trans-prostenoate.
 28. A compound according to claim 6, nat.-15S,16R (and ent.-15R,16S)-9α,15-dihydroxy-11-oxo-15,16-tetramethylene-13-trans-prostenoic acid.
 29. A compound according to claim 6, nat.-15S,16R-9α,15-dihydroxy-11-oxo-15,16-tetramethylene-13-trans-prostenoic acid.
 30. A compound according to claim 6, methyl nat.-15S,16R (and ent.-15R,16S)-9α,15-dihydroxy-11-oxo-15,16-tetramethylene-13-trans-prostenoate.
 31. A compound according to claim 6, methyl nat.-15S,16R-9α,15-dihydroxy-11-oxo-15,16-tetramethylene-13-trans-prostenoate.
 32. A compound according to claim 6, nat.-15S,16S (and ent.-15R,16R)-9α,15-dihydroxy-11-oxo-15,16-tetramethylene-13-trans-prostenoic acid.
 33. A compound according to claim 6, nat.-15S,16S-9α,15-dihydroxy-11-oxo-15,16-tetramethylene-13-trans-prostenoic acid.
 34. A compound according to claim 6, methyl nat.-15S,16S (and ent.-15R,16R)-9α,15-dihydroxy-11-oxo-15,16-tetramethylene-13-trans-prostenoate.
 35. A compound according to claim 6, methyl nat.-15S,16S-9α,15-dihydroxy-11-oxo-15,16-tetramethylene-13-trans-prostenoate.
 36. A compound according to claim 6, nat.-15S,17R (and ent.-15R,17S)-9α,15-dihydroxy-11-oxo-15,17-trimethylene-19,20-dinor-13-trans-prostenoic acid.
 37. A compound according to claim 6, nat.-15S,17R-9α,15-dihydroxy-11-oxo-15,17-trimethylene-19,20-dinor-13-trans-prostenoic acid.
 38. A compound according to claim 6, methyl nat.-15S,17R (and ent.-15R,17S)-9α,15-dihydroxy-11-oxo-15,17-trimethylene-19,20-dinor-13-trans-prostenoate.
 39. A compound according to claim 6, methyl nat.-15S,17R-9α,15-dihydroxy-11-oxo-15,17-trimethylene-19,20-dinor-13-trans-prostenoate.
 40. A compound according to claim 6, nat.-15S,17S (and ent.-15R,17R)-9α,15-dihydroxy-11-oxo-15,17-trimethylene-19,20-dinor-13-trans-prostenoic acid.
 41. A compound according to claim 6, nat.-15S,17S-9α,15-dihydroxy-11-oxo-15,17-trimethylene-19,20-dinor-13-trans-prostenoic acid.
 42. A compound according to claim 6, methyl nat.-15S,17S (and ent.-15R,17R)-9α,15-dihydroxy-11-oxo-15,17-trimethylene-19,20-dinor-13-trans-prostenoate.
 43. A compound according to claim 6, methyl nat.-15S,17S-9α,15-dihydroxy-11-oxo-15,17-trimethylene-19,20-dinor-13-trans-prostenoate.
 44. A compound according to claim 7, nat.-16R,17S (and ent.-16S,17R)-9α,16-dihydroxy-11-oxo-16,17-trimethylene-20-methyl-13-trans-prostenoic acid.
 45. A compound according to claim 7, nat.-16R,17S-9α,16-dihydroxy-11-oxo-16,17-trimethylene-20-methyl-13-trans-prostenoic acid.
 46. A compound according to claim 7, methyl nat.-16R,17S (and ent.-16S,17R)-9α,16-dihydroxy-11-oxo-16,17-trimethylene-20-methyl-13-trans-prostenoate.
 47. A compound according to claim 7, methyl nat.-16R,17S-9α,16-dihydroxy-11-oxo-16,17-trimethylene-20-methyl-13-trans-prostenoate.
 48. A compound according to claim 7, nat.-16R,17R (and ent.-16S,17S)-9α,16-dihydroxy-11-oxo-16,17-trimethylene-20-methyl-13-trans-prostenoic acid.
 49. A compound according to claim 7, nat.-16R,17R-9α,16-dihydroxy-11-oxo-16,17-trimethylene-20-methyl-13-trans-prostenoic acid.
 50. A compound according to claim 7, methyl nat.-16R,17R (and ent.-16S,17S)-9α,16-dihydroxy-11-oxo-16,17-trimethylene-20-methyl-13-trans-prostenoate.
 51. A compound according to claim 7, methyl nat.-16R,17R-9α,16-dihydroxy-11-oxo-16,17-trimethylene-20-methyl-13-trans-prostenoate.
 52. A compound according to claim 3 wherein Z is ##STR34## wherein q is as previously defined.
 53. A compound according to claim 52 wherein q is
 3. 54. A compound according to claim 53 wherein w is zero.
 55. A compound according to claim 53 wherein w is one.
 56. A compound according to claim 54, nat.-15S,16S (and ent.-15R,16R)-9α,15-dihydroxy-11-oxo-15,16-trimethylene-5-cis-13-trans-prostadienoic acid.
 57. A compound according to claim 54, nat.-15S,16S-9α,15-dihydroxy-11-oxo-15,16-trimethylene-15-cis-13-trans-prostadienoic acid.
 58. A compound according to claim 54, methyl nat.-15S,16S (and ent.-15R,16R)-9α,15-dihydroxy-11-oxo-15,16-trimethylene-5-cis-13-trans-prostadienoate.
 59. A compound according to claim 54, methyl nat.-15S,16S-9α,15-dihydroxy-11-oxo-15,16-trimethylene-5-cis-13-trans-prostadienoate.
 60. A compound according to claim 54, nat.-15S,17R (and ent.-15R,17S)-9α,15-dihydroxy-11-oxo-15,17-dimethylene-5-cis-13-trans-prostadienoic acid.
 61. A compound according to claim 54, nat.-15S,17R-9α,15-dihydroxy-11-oxo-15,17-dimethylene-5-cis-13-trans-prostadienoic acid.
 62. A compound according to claim 54, methyl nat.-15S,17R (and ent.-15R,17S)-9α,15-dihydroxy-11-oxo-15,17-dimethylene-5-cis-13-trans-prostadienoate.
 63. A compound according to claim 54, methyl nat.-15S,17R-9α,15-dihydroxy-11-oxo-15,17-dimethylene-5-cis-13-trans-prostadienoate.
 64. A compound according to claim 54, nat.-15S,17S (and ent.-15R,17R)-9α,15-dihydroxy-11-oxo-15,17-dimethylene-5-cis-13-trans-prostadienoic acid.
 65. A compound according to claim 54, nat.-15S,17S-9α,15-dihydroxy-11-oxo-15,17-dimethylene-5-cis-13-trans-prostadienoic acid.
 66. A compound according to claim 54, methyl nat.-15S,17S (and ent.-15R,17R)-9α,15-dihydroxy-11-oxo-15,17-dimethylene-5-cis-13-trans-prostadienoate.
 67. A compound according to claim 54, methyl nat.-15S,17S-9α,15-dihydroxy-11-oxo-15,17-dimethylene-5-cis-13-trans-prostadienoate.
 68. A compound according to claim 54, nat.-15S,16R (and ent.-15R,16S)-9α,15-dihydroxy-11-oxo-15,16-tetramethylene-5-cis-13-trans-prostadienoic acid.
 69. A compound according to claim 54, nat.-15S,16R-9α,15-dihydroxy-11-oxo-15,16-tetramethylene-5-cis-13-trans-prostadienoic acid.
 70. A compound according to claim 54, methyl nat.-15S,16R (and ent.-15R,16S)-9α,15-dihydroxy-11-oxo-15,16-tetramethylene-5-cis-13-trans-prostadienoate.
 71. A compound according to claim 54, methyl nat.-15S,16R-9α,15-dihydroxy-11-oxo-15,16-tetramethylene-5-cis-13-trans-prostadienoate.
 72. A compound according to claim 54, nat.-15S,16S (and ent.-15R,16R)-9α,15-dihydroxy-11-oxo-15,16-tetramethylene-5-cis-13-trans-prostadienoic acid.
 73. A compound according to claim 54, nat.-15S,16S-9α,15-dihydroxy-11-oxo-15,16-tetramethylene-5-cis-13-trans-prostadienoic acid.
 74. A compound according to claim 54, methyl nat.-15S,16S (and ent.-15R,16R)-9α,15-dihydroxy-11-oxo-15,16-tetramethylene-5-cis-13-trans-prostadienoate.
 75. A compound according to claim 54, methyl nat.-15S,16S-9α,15-dihydroxy-11-oxo-15,16-tetramethylene-5-cis-13-trans-prostadienoate.
 76. A compound according to claim 54, nat.-15S,17R (and ent.-15R,17S)-9α,15-dihydroxy-11-oxo-15,17-trimethylene-19,20-dinor-5-cis-13-trans-prostadienoic acid.
 77. A compound according to claim 54, nat.-15S,17R-9α,15-dihydroxy-11-oxo-15,17-trimethylene-19,20-dinor-5-cis-13-trans-prostadienoic acid.
 78. A compound according to claim 54, methyl nat.-15S,17R (and ent.-15R,17S)-9α,15-dihydroxy-11-oxo-15,17-trimethylene-19,20-dinor-5-cis-13-trans-prostadienoate.
 79. A compound according to claim 54, methyl nat.-15S,17R-9α,15-dihydroxy-11-oxo-15,17-trimethylene-19,20-dinor-5-cis-13-trans-prostadienoate.
 80. A compound according to claim 54, nat.-15S,17S (and ent.-15R,17R)-9α,15-dihydroxy-11-oxo-15,17-trimethylene-19,20-dinor-5-cis-13-trans-prostadienoic acid.
 81. A compound according to claim 54, nat.-15S,17S-9α,15-dihydroxy-11-oxo-15,17-trimethylene-19,20-dinor-5-cis-13-trans-prostadienoic acid.
 82. A compound according to claim 54, methyl nat.-15S,17S (and ent.-15R,17R)-9α,15-dihydroxy-11-oxo-15,17-trimethylene-19,20-dinor-5-cis-13-trans-prostadienoate.
 83. A compound according to claim 54, methyl nat.-15S,17S-9α,15-dihydroxy-11-oxo-15,17-trimethylene-19,20-dinor-5-cis-13-trans-prostadienoate.
 84. A compound according to claim 54, nat.-15S,16R (and ent.-15R,16S)-9α,15-dihydroxy-11-oxo-15,16-trimethylene-5-cis-13-trans-prostadienoic acid.
 85. A compound according to claim 54, nat.-15S,16R-9α,15-dihydroxy-11-oxo-15,16-trimethylene-5-cis-13-trans-prostadienoic acid.
 86. A compound according to claim 54, methyl nat.-15S,16R (and ent.-15R,16S)-9α,15-dihydroxy-11-oxo-15,16-trimethylene-5-cis-13-trans-prostadienoate.
 87. A compound according to claim 54, methyl nat.-15S,16R-9α,15-dihydroxy-11-oxo-15,16-trimethylene-5-cis-13-trans-prostadienoate.
 88. A compound according to claim 55, nat.-16R,17R (and ent.-16S,17S)-9α,16-dihydroxy-11-oxo-16,17-trimethylene-20-methyl-5-cis-13-trans-prostadienoic acid.
 89. A compound according to claim 55, nat.-16R,17R-9α,16-dihydroxy-11-oxo-16,17-trimethylene-20-methyl-5-cis-13-trans-prostadienoic acid.
 90. A compound according to claim 55, methyl nat.-16R,17R (and ent.-16S,17S)-9α,16-dihydroxy-11-oxo-16,17-trimethylene-20-methyl-5-cis-13-trans-prostadienoate.
 91. A compound according to claim 55, methyl nat.-16R,17R-9α,16-dihydroxy-11-oxo-16,17-trimethylene-20-methyl-5-cis-13-trans-prostadienoate.
 92. A compound according to claim 55, nat.-16R,17S (and ent.-16S,17R)-9α,16-dihydroxy-11-oxo-16,17-trimethylene-20-methyl-5-cis-13-trans-prostadienoic acid.
 93. A compound according to claim 55, nat.-16R,17S-9α,16-dihydroxy-11-oxo-16,17-trimethylene-20-methyl-5-cis-13-trans-prostadienoic acid.
 94. A compound according to claim 55, methyl nat.-16R,17S (and ent.-16S,17R)-9α,16-dihydroxy-11-oxo-16,17-trimethylene-20-methyl-5-cis-13-trans-prostadienoate.
 95. A compound according to claim 55, methyl nat.-16R,17S-9α,16-hydroxy-11-oxo-16,17-trimethylene-20-methyl-5-cis-13-trans-prostadienoate.
 96. The compound nat.-15S,17S-(and ent.-15R,17R)-9α,15-dihydroxy-11-oxo-4-methyl-15,17-trimethylene-19,20-dinor-5-cis-13-trans-prostadienoic acid.
 97. The compound nat.-15S,17R-(and ent.-15R,17S)-9α,15-dihydroxy,11-oxo-4-methyl-15,17-trimethylene-19,20-dinor-5-cis-13-trans-prostadienoic acid. 